Patent Application
20050250792
The present invention relates to substituted piperidine compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
The C-X-C chemokines include several potent chemoattactants and activators of neutrophils such as interleukin-8 (IL-8) and neutophil-activating peptide 2 (NAP-2).
The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β).
Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
The present invention provides a compound of formula (I):
Certain compounds of formula (I) are capable of existing in isomeric forms (for example as tautomers, enantiomers, geometric isomers or diastereomers). The present invention encompasses all such isomers and mix thereof in all proportions.
Hydroxyalkyl is, for example, 2-hydoxyeth-1-yl. Haloalkyl is, for example, CF3. Alkoxy is, for example, methoxy or ethoxy. Alkoxy(C1-C6 alkyl) is, for example, methoxymethyl or ethoxyethyl. Cycloalkyl is, for example, cyclopropyl or cyclohexyl. Cycloalkyl(C1-C6 alkyl) is, for example, cyclopropylmethyl. Alkylthio is, for example, methylthio or ethylthio. Alkylthio(C1-C6 alkyl) is, for example, methylthiomethyl. Alkylcarbonyloxy(C1-C6 alkyl) is, for example, CH3C(O)OCH2. S(O)2(alkyl) is, for example, CH3S(O)2. AlkylS(O)2(C1-C6 alkyl) is, for example, CH3S(O)2CH2. Aryl(C1-C6 alkyl) is, for example, benzyl, 2-phenyleth-1-yl or 1-phenyleth-1-yl. Hetrocyclyl(C1-C6 alkyl) is, for example, heterocyclylmethyl. ArylS(O)2(C1-C6 alkyl) is, for example, phenylS(O)2CH2. HeterocyclylS(O)2(C1-C6 alkyl) is, for example, heterocyclylS(O)2CH2. Aryl(C1-C6 alkyl)S(O)2 is, for example, benzylS(O)2. Heterocyclyl(C1-C6 alkyl)S(O)2 is, for example, heterocyclylCH2S(O)2. Alkenyl is, for example, vinyl or allyl. Carboxy-substituted C1-C6 alkoxy is, for example, HOC(O)CH2CH2O. Haloalkoxy is, for example, OCF3. Hydroxyalkoxy is, for example, HOCH2CH2O. Alkylcarboxy-substituted C1-C6 alkoxy is, for example, CH3OC(O)CH2CH2O. Aryloxy is, for example, phenoxy.
Heterocyclyloxy is, for example, pyridinyloxy or pyrimidinyloxy. C3-C7 cycloalkyl(C1-C6 alkylthio) is, for example, cyclopropylCH2S. Alkynylthio is, for example, propargylthio. Alkylcarbonylamino is, for example, acylamino. Haloalkylcarbonylamino is, for example, ClCH2C(O)NH. Alkoxycarbonyl is, for example, CH3OC(O).
Aryl is a carbocyclic aromatic ring optionally fused to one or more carbocyclic rings. Aryl is, for example, phenyl, naphthyl or indanyl.
Heterocyclyl is an aromatic or non-aromatic ring system preferably comprising up to 6 (preferably up to 4) heteroatoms selected from the group comprising nitrogen, oxygen and sulphur, and preferably comprising one, two or three 5- or 6-membered rings. Heterocyclyl is, for example, furyl, thienyl pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetratolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl (for example 2-pyridinyl, 3-pyridinyl or 4-pyridinyl), pyrimidiyl (for example 2-pyrimidinyl or 4-pyrimidinyl), pyrazinyl, pyridazinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl, benz[b]thienyl, 2,3-dihydrobenz[b]thienyl (for example 1-dioxo-2,3-dihydrobenz[b]thienyl), benzimidazolyl, benzatriazolyl, benzoxazolyl, benzthiazolyl, 2,3-dihydrobenzthiazolyl (for example 2,3-dihydrobenzthiazol-2-onyl which is also known as 2-oxo-1,3-benzothiazol-3(2H)-yl), 1,2,3-benzothiadiazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzothiadiazolyl, 2,1,3-benzoxadiazolyl, quinoxalinyl dihydro-1-benzopyryliumyl (for example a coumarinyl or a chromenonyl), 1,3-benzodioxolyl (also known as 1,2-methylenedioxyphenyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example 2-dioxo-3,4-dihydro-1H-2,1 -benzothiazinyl), purine (for example 1H-purine or 9H-purine), 1H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, quinolinyl (for example 2-quinolinyl, 3-quinolinyl or 4-quinolinyl), isoquinolinyl, quinazolinyl or dibenzothiophenyl; or a ring as shown below:
The group R1 may represent an optionally substituted 3- to 14-membered (especially 5- to 10-membered) saturated or unsaturated ring system which optionally comprises one or two ring carbon atoms that form carbonyl groups and which optionally further comprises one, two, three or four ring heteroatoms independently selected from nitrogen, oxygen and sulphur. Examples of R1 ring systems, which can be moncyclic or polycyclic, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, indanyl, furyl, thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1,2,4-oxadiazlyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl (for example 2-pyridinyl, 3-pyridinyl or 4-pyridinyl), pyrimidinyl (for example 2-pyrimidinyl or 4-pyrimidinyl), pyrazinyl, pyridazinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl, benz[b]thienyl, 2,3-dihydrobenz[b]thienyl (for example 1-dioxo-2,3-dihydrobenz[b]thienyl), benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 2,3-dihydrobenzthiazolyl (for example 2,3-dihydrobenzthiazol-2-onyl which is also known as 2-oxo-1,3-benzothiazol-3(2H)-yl), 1,2,3-benzothiadiazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzothiadiazolyl, 2,1,3-benzoxadiazolyl, quinoxalinyl, dihydro-1-benzopyryliumyl (for example a coumarinyl or a chromenonyl), 1,3-benzodioxolyl (also known as 1,2-methylenedioxyphenyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), purine (for example 1H-purine or 9H-purine), 1H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, quinolinyl (for example 2qunolinyl, 3-quinolinyl or 4-quinolinyl), isoquinolnyl, quinazolinyl or dibenzothiophenyl; or a ring as shown below:
In one aspect the present invention provides a compound of formula (Ia):
In the context of the present specification, unless otherwise indicated an alkyl substituent or an alkyl moiety in a substituent group may be linear or branched. Examples of alkyl groups/moieties containing up to twelve carbon atoms include methyl, ethyl n-propyl, iso propyl, n-butyl, isobutyl tert-butyl n-pentyl n-hexyl, n-heptyl, n-octyl, n-nonyl n-decyl n-undecyl and n-dodecyl groups. A C1-C6 hydroxyalkyl group will comprise at least one hydroxyl group (e.g. one, two or three hydroxyl groups) which may be attached to an internal or terminal carbon atom of the alkyl chain. Similarly, a carboxy-substituted C1-C6 alkoxy group will comprise at least one carboxyl group (e.g. one, two or three carboxyl groups) which may be attached to an internal or terminal carbon atom of the alkyl chain. A C1-C6 haloalkyl or C1-C6 haloalkoxy group will comprise at least one halogen atom (e.g. one, two, three or four halogen atoms independently selected from fluorine, chlorine, bromine and iodine) which may be attached to an internal or terminal carbon atom of the alkyl chain. A halophenyl group will comprise from 1 to 5 halogen atoms independently selected from fluorine, chlorine, bromine and iodine. A C1-C6 alkylbenzyl group will comprise at least one C1-C6 alkyl group (e.g. one, two or three C1-C6 alkyl groups) attached to the phenyl ring of the benzyl moiety. If there is more than one C1-C6 alkyl group attached to the phenyl ring, the groups may be the same or different. In a C1-C6 alkoxycarbonylpiperazinyl substituent group, the piperazinyl moiety is attached through a nitrogen atom to the carbonyl moiety. When T represents C(O)NR9, it should be understood that the nitrogen atom is attached directly to the six-membered heterocyclic ring in formula (I).
The group R1 may represent a C1-C12, preferably C1-C10, more preferably C1-C6, alkyl group optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from cyano, hydroxyl, C1-C6, preferably C1-C4, alkoxy, C1-C6, preferably C1-C4, alkylthio and C1-C6 alkoxycarbonyl, preferably C1-C4 alkoxycarbonyl.
The group R1 may alternatively represent an optionally substituted 3- to 10-membered saturated or unsaturated ring system which optionally comprises one or two ring carbon atoms that form carbonyl groups and which optionally further comprise one, two, three or four ring heteroatoms independently selected from nitrogen, oxygen and sulphur. Examples of ring systems that may be used which can be moncyclic or polycyclic include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazolyl, furyl, thienyl, imidazolyl, quinolinyl (e.g. 2-quinolinyl, 3-quinolinyl or 4-quinolinyl), pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl or 4-pyridinyl), 1,3-benzodioxolyl, thiazolyl, benzimidazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl), triazolyl (such as 1,2,3-triazolyl or 1,2,4-triazolyl), benzothiazolyl, pyrimidinyl (e.g. 2-pyrimidinyl or 4-pyrimidinyl), benzothienyl,
In a further aspect of the invention the ring system of R1 may be optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine); cyano; nitro; hydroxyl; carboxyl; C1-C6, preferably C1-C4, alkyl (especially methyl or ethyl); C1-C6, preferably C1-C4, hydroxyalkyl; C1C6, preferably C1-C4, haloalkyl (e.g. trifluoromethyl); C1-C6, preferably C1-C4, alkoxy (especially methoxy, ethoxy, n-propoxy or isopropoxy); carboxy-substituted C1-C4, preferably C1C4, alkoxy; C1-C6, preferably C1-C4, alkylthio (especially methylthio, ethylthio, n-propylthio and tert-butylthio); C1-C6, preferably C1-C4, alkylthiomethyl particularly methylthiomethyl); C1-C6, preferably C1-C4, alkylcarbonylamino (especially methylcabonylamino); —NR7R8; —C(O)NR7R8; C1-C6, preferably C1-C4, alkylcarbonyloxymethyl (particularly methylcarbonyloxymethyl); C1-C6, preferably C1-C4, alkoxycarbonyl (especially methoxycarbonyl or ethoxycarbonyl); C1-C6, preferably C1C4, alkoxycarbonylpiperazinyl; furyl; phenyl; pyridinyl; pyrazinyl; halophenyl (especially chlorophenyl); thienyl; thienylmethyl; C1-C6, preferably C1-C4, alkylbenzyl (particularly methylbenzyl); and
In a further aspect R1 is an aromatic 5-membered heterocyclyl having 2, 3 or 4 ring nitrogen atoms (for example 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole or tetrazole) substituted by one heteroaromatic ring (such as pyridine or pyrazole) which is itself optionally substituted by halogen or C1-C4 alkyl; or R1 is halophenyl (for example phenyl optionally substituted (such as in the 4-position) by fluoro or chloro; such as 4-chlorophenyl or 4-fluorophenyl).
In a further aspect of the invention Q is oxygen or m is 0. In another aspect of the invention Q represents a sulphur atom or a group NH, C(O) or NHC(O).
In yet another aspect of the invention n is 1 or 2.
In a further aspect of the invention T represents a group NH, C(O)NH or NHC(O)NH. In another aspect of the invention T repents a NH or C(O)NH group. In a further aspect T is C(O)NH.
In one aspect X1, X2, X3 and X4 are all CH2 or CHR12, wherein the R12 groups of X1 and X3 or X4, or, X2 and X3 or X4 join to form CH2CH2; provided always that at least two of X1, X2, X3 and X4 are CH2. In a still further aspect X1, X2, X3 and X4 are al CH2. Preferably, all four groups X represent CH2.
It is preferred that each R2 and R3 independently represents a hydrogen atom or a methyl group, especially a hydrogen atom.
In one aspect R4 and R5 are hydrogen or C1-C4 alkyl. In another aspect R4 and R5 preferably each represent a hydrogen atom.
In another aspect of the invention R6 represents a phenyl group optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), amino, nitro, cyano, sulphonyl, sulphonamido, C1-C6, preferably C1-C4, alkyl, C1-C6, preferably C1-C4, haloalkoxy, methylenedioxy and C1-C6, preferably C1-C4, alkylsulphonyl.
In another aspect of the invention R6 represents a phenyl group optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), amino, nitro, cyano, sulphonyl, sulphonamido, C1-C6, preferably C1-C4 alkyl, C1-C6, preferably C1-C4, haloalkoxy and C1-C6, preferably C1-C4, alkylsulphonyl.
In a further aspect R1 is phenyl optionally substituted by halogen or methylenedioxy. In a still further aspect R6 is most preferably a phenyl group substituted by halogen. Examples of R6 include 3-chlorophenyl, chlorophenyl or, especially, 3,4-dichlorophenyl.
R7 and R8 each independently represent a hydrogen atom or a group selected from C1-C6, preferably C1-C4, hydroxyalkyl C3-C6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) and C1-C6, preferably C1-C4, alkyl optionally substituted by phenyl (e.g. one or two phenyl groups).
Most preferably, R7 and R8 each independently represent a hydrogen atom, or a group selected from C2 hydroxyalkyl, cyclopropyl and C1-C2 alkyl optionally substituted by phenyl.
Compounds of the invention include all the Examples below, some of which are:
The present invention further provides a process for the preparation of a compound of formula (I) or (Ia) which comprises:
Compounds of formulae (II) to (XIV) are either commercially available, or are known in the literature or may be prepared using known techniques.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) or (Ia) may involve, at an appropriate stage, the addition and subsequent removal of one or more protecting groups.
The protection and deprotection of functional groups is described in ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOrnie, Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).
The compounds of the invention and intermediates may be isolated from their reaction mixtures, and if necessary further purified, by using standard techniques.
The compounds of formula (I) and (Ia) have activity as pharmaceuticals, in particular as modulators of chemokine receptor activity. More particularly, the compounds have utility as modulators of the activity of chemokine receptors CCR1 and/or CCR3.
A further aspect of the invention involves the use of a compound of formula (I) or (Ia) in the treatment of conditions or diseases in which modulation of chemokine receptor activity is beneficial.
Thus, compounds of formula (I) or (Ia) may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS). Examples of these conditions include:
Thus, the present invention provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a salt thereof; as hereinbefore defined for use in therapy.
In a further aspect, the present invention provides the use of a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a salt thereof; as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be construed accordingly.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
In another aspect the present invention provides the use of a compound of formula (I), wherein Z is CR4R5, C(O) or CR4R5-Z1; Z1 is C1-4 alkylene, C2-4 alkenylene or C(O)NH; R1 represents a C1-C12 alkyl group optionally substituted by one or more substituents independently selected from cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-7 cycloalkyl, C1-C6 alkoxycarbonyl and phenyl (itself optionally substituted by one or more of halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, phenyl(C1-C6 alkyl), C1-C6 alkoxy, C1-C6 haloalkoxy, S(O)2(C1-C6 alkyl), C(O)NH2, carboxy or C1-C6 alkoxycarbonyl); or R1 represents C2-C6 alkenyl optionally substituted by phenyl (itself optionally substituted by one or more of halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl phenyl(C1-C6 alkyl), C1-C6 alkoxy, C1-C6 haloalkoxy, S(O)2(C1-C6 alkyl), C(O)NH2, carboxy or C1-C6 alkoxycarbonyl); or R1 represents a 3- to 14-membered saturated or unsaturated ring system which optionally comprises up to two ring carbon atoms that form carbonyl groups and which optionally further comprises up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, wherein the ring system is optionally substituted by one or more substituents independently selected from: halogen, cyano, nitro, oxo, hydroxyl, C1-C8 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy(C1-C6 alkyl), C3-C7 cycloalkyl(C1-C6 alkyl), C1-C6 alkylthio(C1-C6 alkyl), C1-C6 alkylcarbonyloxy(C1-C6 alkyl), C1-C6 alkylS(O)2(C1-C6 alkyl), aryl(C1-C6 alkyl), heterocyclyl(C1-C6 alkyl), arylS(O)2(C1-C6 alkyl), heterocyclylS(O)2(C1-C6 alkyl), aryl(C1-C6 alkyl)S(O)2, hetercyclyl(C1-C6 alkyl)S(O)2, C2-C6 alkenyl, C1-C6 alkoxy, carboxy-substituted C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkoxy, C1-C6 alkylcarboxy-substituted C1-C6 alkoxy, aryloxy, hetercyclyloxy, C1-C6 alkylthio, C3-C7 cycloalkyl(C1-C6 alkylthio), C3-C6 alkynylthio, C1-C6 alkylcarbonylamino, C1-C6 halolylcarbonylamino, SO3H, —NR7R8, —C(O)NR23R24, S(O)2NR18R19, S(OR)2R20, R25C(O), carboxyl C1-C6 alkoxycarbonyl, aryl and heterocyclyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, oxo, hydroxy, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, phenyl(C1-C6 alkyl), C1-C6 alkoxy, C1-C6 haloalkoxy, S(O)2(C1-C6 alkyl), C(O)NH2, carboxy or C1-C6 alkoxycarbonyl; m is 0 or 1; Q represents an oxygen or sulphur atom or a group NR9, C(O), C(O)NR9, NR9C(O) or CH═CH; n is 0, 1, 2, 3, 4, 5 or 6 provided that when n is 0, then m is 0; each R2 and R3 independently represents a hydrogen atom or a C1-C4 alkyl group, or (CR2R3)n represents C3-C7 cycloalkyl optionally substituted by C1-C4 alkyl; T represents a group NR10, C(O)NR10, NR11C(O)NR10 or C(O)NR10NR11; X1, X2, X3 and X4 are, independently, CH2, CHR12 (wherein each R12 is, independently, C1-C4 alkyl or C3-C7 cycloalkyl(C1-C4 alkyl)) or C═O; or, when they are CHR12, the R12 groups of X1 and X3 or X4, or, X2 and X3 or X4 join to form a two or three atom chain which is CH2CH2, CH2CH2CH2, CH2OCH2 or CH2SCH2; provided always that at least two of X1, X2, X3 and X4 are CH2; R4 and R5 each independently represent a hydrogen atom or a C1-C4 alkyl group; R6 is aryl or heterocyclyl, both optionally substituted by one or more of: halogen, cyano, nitro, oxo, hydroxyl, C1-C8 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 alkoxy(C1-C6 alkyl), C3-C7 cycloalkyl(C1-C6 alkyl), C1-C6 alkylthio(C1-C6 alkyl), C1-C6 alkylcarbonyloxy(C1-C6 alkyl), C1-C6 alkylS(O)2(C1-C6 alkyl), aryl(C1-C6 alkyl), heterocyclyl(C1-C6 alkyl), arylS(O)2(C1-C6 alkyl), heterocyclylS(O)2(C1-C6 alkyl), aryl(C1-C6 alkyl)S(O)2, heterocyclyl(C1-C6 alkyl)S(O)2, C2-C6 alkenyl, C1-C6 alkoxy, carboxy-substituted C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkoxy, C1-C6 alkylcarboxy-substituted C1-C6 alkoxy, aryloxy, heterocyclyloxy, C1-C6 alkylthio, C3-C7 cycloalkyl(C1-C6 alkylthio), C3-C6 alkynylthio, C1-C6 alkylcarbonylamino, C1-C6 haloalkylcarbonylamino, SO3H, —NR16R17, —C(O)NR21R22, S(O)2NR13R14, S(O)2R15, R26C(O), aroxyl, C1-C6 alkoxycarbonyl, aryl and heterocyclyl; is wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, phenyl(C1-C6 alkyl), C1-C6 alkoxy, C1-C6 haloalkoxy, S(O)2(C1-C6 alkyl), C(O)NH2, carboxy or C1-C6 alkoxycarbonyl; R7, R8, R9, R10, R11, R13, R14, R16, R17, R18, R19, R21, R22, R23 and R24 are, independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C7 cycloalkyl, C3-C7 Cycloalkyl(C1-C4 alkyl) or phenyl(C1-C6 alkyl); R15 and R20 are, independently, C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl) or C1-C6 alkyl optionally substituted by phenyl; and, R25 and R26 are, independently, C1-C6 alkyl or phenyl (optionally substituted by one or more of halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, phenyl(C1-C6 alkyl), C1-C6 alkoxy, C1-C6 haloalkoxy, S(O)2(C1-C6 alkyl), C(O)NH2, carboxy or C1-C6 alkoxycarbonyl); or a pharmaceutically acceptable salt thereof or solvate thereof or a solvate of a salt thereof, in the manufacture of a medicament for the modulation of a chemokine receptor (such as CCR1 or CCR3). In a further aspect such medicament is for the treatment of asthma.
The invention also provides a method of treating an inflammatory disease in a person suffering from, or at risk of, said disease, which comprises administering to the person a therapeutically effective amount of a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof a solvate thereof or a solvate of a salt thereof, as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
A compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or solvate of a salt, may be used on its own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) or (Ia) compound, salt, solvate or solvate of salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate or solvate of salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders, aerosols or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.
The present invention will be further explained by reference to she following illustrative examples.
Sodium triacetoxyborobydride (6 g) was added to a stir solution of 3,4-dichlorobenzaldehyde (4.2 g) and 1,1-dimethylethyl 4-piperidinyl carbamate (4 g) in dichloromethane (50 ml). The mixture was stirred at room temperature for 4 h then partitioned between ethyl acetate and aqueous sodium hydrogencarbonate. The organic layer was washed with water, dried and evaporated under reduced pressure. The residue was triturated with ether to give a white solid (3.5 g). Used directly.
The product from step (i) (3.5 g) was treated with trifluoroacetic acid (10 ml) in dichloromethane (40 ml). After 72 h, the solution was evaporated, the residue triturated with ether and the solid (4.3 g) collected.
MS: APCI(+ve) 259/61 (M+1)
The product from step (ii) (2 mg), the appropriate aldehyde (2 equivalents), sodium triacetoxyborohydride (3 equivalents) and diisopropylethylamine (2 equivalents) in acetonitrile (0.08 ml) and 1-methyl-2-pyrrolidinone (0.12 ml) was left at room temperature for 24 h. The reaction mixture was evaporated to dryness and the residue dissolved in dimethylsuphoxide (0.4 ml).
MS: AP.CI(+ve) 363 (M+1)
MS: APCI(+ve) 406 (M+1)
MS: APCI(+ve) 365 (M+1)
MS: APCI(+ve) 389 (M+1)
MS: APCI(+ve) 353 (M+1)
MS: APCI(+ve) 394 (M+1)
MS: APCI(+ve) 349 (M+1)
MS: APCI(+ve) 367 (M+1)
MS: APCI(+ve) 419 (M+1)
MS: APCI(+ve) 419 (M+1)
MS: APCI(+ve) 350 (M+1)
MS: APCI(+ve) 369 (M+1)
MS: APCI(+ve) 369 (M+1)
MS: APCI(+ve) 395 (M+1)
MS: APCI(+ve) 410 (M+1)
MS: APCI(+ve) 417 (M+1)
MS: APCI(+ve) 403 (M+1)
MS: APCI(+ve) 373 (M+1)
MS: APCI(+ve) 443 (M+1)
MS: APCI(+vc) 414 (M+1)
MS: APCI(+ve) 434 (M+1)
MS: APCI(+ve) 364 (M+1)
MS: APCI(+ve) 400 (M+1)
MS: APCI(+ve) 411 (M+1)
MS: APCI(+ve) 459 (M+1)
MS: APCI(+ve) 350 (M+1)
MS:APCI(+ve) 410(M+1)
MS: APCI(+ve) 437 (M+1)
MS: APCI(+ve) 377 (M+1)
MS: APCI(+ve) 409 (M+1)
MS: APCI(+ve) 393 (M+1)
MS: APCI(+ve) 356 (M+1)
MS: APCI(+ve) 367 (M+1)
MS: APCI(+ve) 400 (M+1)
MS: APCI(+ve) 400 (M+1)
MS: APCI(+ve) 439 (M+1)
MS: APCI(+ve) 419 (M+1)
MS: APCI(+ve) 453 (M+1)
MS: APCI(+ve) 433 (M+1)
MS: APCI(+ve) 475 (M+1)
MS: APCI(+ve) 445 (M+1)
MS: APCI(+ve) 407 (M+1)
MS: APCI(+ve) 403 (M+1)
MS: APCI(+ve) 363 (M+1)
MS: APCI(+ve) 350 (M+1)
MS: APCI(+vc) 377 (M+1)
MS: APCI(+ve) 425 (M+1)
Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (2 equiv) was added to a solution of the product from Example 1 step (ii) (hydrochloride salt) (1 mg), the appropriate acid (2 equivalents) and diisopropylethylamine (5 equivalents) in dimethylformamide (0.17 ml) and was left at room temperature for 24 h. The reaction mixture was evaporated to dryness and the residue dissolved in dimethylsulphoxide (0.3 ml).
MS: APCI(+ve) 353 (M+1)
MS: APCI(+ve) 474 (M+1)
MS: APCI(+ve) 611 (M+1)
MS: APCI(+ve) 444 (M+1)
MS: APCI(+ve) 480 (M+1)
MS: APCI(+ve) 486 (M+1)
MS: APCI(+ve) 480 (M+1)
MS: APCI(+ve) 437 (M+1)
MS: APCI(+ve) 407 (M+1)
MS: APCI(+ve) 486 (M+1)
MS: ACI(+ve) 439 (M+1)
MS: APCI(+ve) 433 (M+1)
MS: APCI(+vc) 465 (M+1)
MS: APCI(+ve) 425 (M+1)
MS: APCI(+vc) 395 (M+1)
MS: APCI(+ve) 510 (M+1)
MS: APCI(+ve) 369 (M+1)
MS: APCI(+ve) 444 (M+1)
MS: APCI(+ve) 411 (M+1)
MS: APCI(+ve) 577 (M+1)
MS: APCI(+ve) 466 (M+1)
MS: APCI(+ve) 448 (M+1)
MS: APCI(+ve) 381 (M+1)
MS: APCI(+ve) 377 (M+1)
MS: APCI(+ve) 377 (M+1)
MS: APCI(+ve) 393 (M+1)
A solution of 3,4-dichlorobenzyl chloride (2.8 ml), 4-ketopiperidine hydrochloride monohydrate and triethylamine (8 ml) in dimethylformamide (30 ml) was stirred at room temperature for 20 h. The mixture was partitioned between water and ethyl acetate, the organic layer dried and evaporated under reduced pressure. Purification was by chromatography eluting with 40-50% ethyl acetate/isohexane. Yield 2.1 g. MS: APCI(+ve) 258/60 (M+1)
A solution of the product from step (i) (1.61 g), N-(tert-butoxycarbonyl)-ethylenediamine (1 g) and sodium triacetoxyborohydride (2.12 g) in dichloromethane (20 ml) was stirred at room temperature for 3 h. The mixture was partitioned between water and ethyl acetate, the organic layer dried and evaporated under reduced pressure. Yield 1.28 g. MS: APCI(+ve) 402/4 (M+1)
The product from step (ii) (128 g) was treated with trifluoroacetic acid (5 ml) in dichloromethane (10 ml). After 20 h, the solution was evaporated, the residue triturated with ether and the solid (1.62 g) collected.
MS: APCI(+ve) 302/4 (M+1)
The product from step (iii) (0.0026 g), the appropriate activated halo-aromatic (1.25 equivalents) and diisopropylethylamine (10 equivalents) in 1-methyl-2-pyrrolidinone (0.15 ml) was heated at 100° C. for 20 h The reaction mixture was evaporated to dryness u and the residue dissolved in dimethylsuphoxide (0.4 ml).
MS: APCI(+ve) 440(M+1)
MS: APCI(+ve) 494(M+1)
MS: APCI(+ve) 456(M+1)
MS: APCI(+ve) 439(M+1)
MS: APCI(+ve) 409(M+1)
MS: APCI(+ve) 423(M+1)
MS: APCI(+ve) 471(M+1)
MS: APCI(+vc) 456(M+1)
MS: APCI(+ve) 448(M+1)
MS: APCI(+ve) 454(M+1)
MS: APCI(+ve) 423(M+1)
MS: APCI(+ve) 435(M+1)
MS: APCI(+ve) 457(M+1)
MS: APCI(+ve) 462(M+1)
MS: APCI(+ve) 462(M+1)
MS: APCI(+ve) 434(M+1)
MS: APCI(+ve) 420(M+1)
MS: APCI(+ve) 450(M+1)
MS: APCI(+ve) 450(M+1)
MS: APCI(+ve) 434(M+1)
Carbonyldiimidazole (0.105 g) was added to a stirred solution of 2-{[5-(trifluoromethyl)-2-pyridinyl]sulfanyl) acetic acid (0.166 g) in dimethylformamide (2 ml). After 1 h a solution of Is the product from Example 1 step (ii) (0.3 g) in a solution of dimethylformamide and diisopropylethylamine (2 equivalents) (1.5 ml) was added and stirred at room temperature for 2 h The mixture was partitioned between water and ethyl acetate, the organic layer washed with water, dried and evaporated under reduced pressure. The residue was triturated with ether and collected Yield 0.084 g as a solid.
MS: APCI(+ve) 478/80 (M+1)
1H NMR: δ (DMSO-d6) 8.76(s, 1H), 8.11 (d, 1H), 8.02(dd, 1H), 7.59-7.53(m, 3H), 7.29(dd, 1H), 3.91(s, 1H), 3.58-3.45(m, 1H), 3.44(s, 2H), 2.70(br d, 2H), 2.03(br t, 2H), 1.70(br d, 2H), 1.46-1.37(m, 2H).
MP: 98° C.
The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and of 2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetic acid (0.151 g) using the method of Example 94.
Yield 0.18 g as a solid.
MS: APCI(+ve) 457/9 (M+1)
1H NMR: δ (DMSO-d6) 7.90(d, 1H), 7.59-7.38(m, 8H), 7.29(dd, 1H), 3.54-3.50(m, 1H), 3.45(s, 2H), 3.24(s, 2H), 2.72(br d, 2H), 224(s, 3H), 2.03(br t, 2H), 1.72(br d, 2H), 1.46-1.37(m, 2H).
MP: 165° C.
The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and of 5-oxo-5-phenylpentanoic acid (0.134 g) using the method of Example 94. Yield 0.149 g as a solid.
MS: APCI(+ve) 433/5 (M+1)
1H NMR: δ (DMSO-d6) 7.96-7.93(m, 2H), 7.72(d, 1H), 7.65-7.50(m, 5H), 7.28(dd, 1H), 3.57-3.48(m, 1H), 3.44(s, 2H), 3.01(t, 2H), 2.72-2.67(m, 2H), 2.13(t, 2H), 2.04-1.98(m, 2H), 1.86-1.79(m, 2H), 1.69(br s, 2H), 1.41-1.32(m, 2H).
MP: 130° C.
The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and 2-[2-(4-chlorophenyl)-5-methyl-1,3-thiazol 4-yl]acetic acid (0.187 g) using the method of Example 94. Yield 0.1 g as a solid.
MS: APCI(+ve) 510/2 (M+1)
1H NMR: δ (DMSO-d6) 8.00(d, 1H), 7.85-7.82(m, 2H), 7.59-7.52(m, 4H), 7.29(dd, 1H), 3.57-3.51(m, 3H), 3.44(s, 2H), 2.72(br d, 2H), 2.41(s, 3H), 2.06(t, 2H), 1.73(br d, 2H), 1.48-1.38(m, 2H).
MP: 170° C.
The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and 2-(phenylsulfanyl)acetic acid (0.118 g) using the method of Example 94. Yield 0.056 g as a solid.
MS: APCI(+ve) 409 (M+1)
1H NMR: δ (DMSO-d6) 8.00(d, 1H), 7.57(d, 1H), 7.53(d, 1H), 7.36-7.27(m, 5H), 7.20-7.16(m, 1H), 3.61(s, 2H), 3.55-3.47(m, 1H), 3.44(s, 2H), 2.69-2.66(m, 2H), 2.02(t, 2H), 1.67-1.64(m, 2H), 1.41-1.31(m, 2H).
The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and 2-(4-fluorophenyl)acetic acid (0.108 g) using the method of Example 94. Yield 0.15 g as a solid.
MS: APCI(+ve) 395 (M+1).
1H NMR: δ (DMSO-d6) 7.98(d, 1H), 7.57(d, 1H), 7.53(d, 1H), 7.30-7.25(m, 3H), 7.13-7.07(m, 2H), 3.54-3.48(m, 1H), 3.45(s, 2H), 3.37(s, 2H), 2.72-2.69(m, 2H), 2.02(t, 2H), 1.71-1.68(m, 2H), 1.44-1.34(m, 2H).
MP: 144-7° C.
The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and 2-[2-(2-pyrazinyl)-1,3-thiazol-4-yl]acetic acid (0.155 g) using the method of Example 94. Yield 0.08 g as a solid.
MS: APCI(+vc) 462 (M+1)
1H NMR: δ (DMSO-d6) 9.25(d, 1H), 8.74-8.71(m, 2H), 8.07(d, 1H), 7.64(s, 1H), 7.59-7.54(m, 2H), 7.31-7.28(m, 1H), 3.69(s, 2H), 3.59-3.54(m, 1H), 3.45(s, 2H), 2.74-2.71(m, 2H), 2.04(t, 2H), 1.76-1.74(m, 2H), 1.49-1.39(m, 2H).
MP: 186-9° C.
The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and 2-[(5-phenyl-2-pyrimidinyl)sulfanyl]acetic acid (0.172 g) using the method of Example 94.
Yield 0.1 15 g as a solid.
MS: APCI(+ve) 487/9 (M+1)
1H NMR: δ (DMSO-d6) 8.96(s, 2H), 8.09(d, 1H), 7.78-7.75(m, 2H), 7.58-7.43(m, 5H), 7.28(dd, 1H), 3.91(s, 2H), 3.59-3.52(m, 1H), 3.44(s, 2H), 2.70(br d, 2H), 2.03(br t, 2H), 1.72(br d, 2H), 1.47-138(m, 2H).
MP: 157° C.
The title compound was prepared from the product of Example 1 step (ii) (0.9 g) and 3-[3-(2-pyridinyl)1,2,4-oxadiazol-5-yl]propanoic acid (0.3 g) using the method of Example 94.
Yield 0.074 g as a solid.
MS: APCI(+ve) 460/2 (M+1)
1H NMR: δ (DMSO-d6) 8.76-8.74(m, 1H), 8.05-7.99(m, 2H), 7.94(d, 1H), 7.61-7.56(m, 2H), 7.52(d, 1H), 7.28(dd, 1H), 3.56-3.48(m, 1H), 3.43(s, 2H), 3.19(t, 2H), 2.71-2.66(m, 4H), 2.03(t,2H), 1.69(brd, 2H), 1.42-133(m, 2H).
MP: 155° C.
A solution of 2-chlorobenzimidazole (1 g) and ethyl 4-amino-1-piperidinecarboxylate (2 g) in 1-methyl-2-pyrrolidinone was heated at 130° C. for 24 h The mixture was partitioned between water and ethyl acetate, the organic layer washed with water, dried and lo evaporated under reduced pressure. Purification was by chromatography eluting with 1% triethylamine/5% methanol in dichloromethane. Yield 0.630 g as a solid.
TOF MS ES+289.1652 (M+1)
The product from step (i) (0.58 g) was heated under reflux with 5M hydrochloric acid (20 ml) for 24 h The solvent was evaporated under reduced pressure, the residue azeotroped with toluene, washed with ether. Yield 0.58 g as a solid.
TOF MS ES+217.1452 (M+1)
Triethylamine (0.223 ml) was added to a stirred suspension of the product from step (ii) (0.2 g) in dimethylformamide. After 5 min 3,4-dichlorobenzaldehyde (0.175 g) then sodium triacetoxyborohydride (0.212 g) was added and the mixture stirred at room temperature for 3 h The mixture was partitioned between 2M hydrochloric acid and ether, the aqueous layer was basified with aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried and evaporated under reduced pressure. The residue was triturated with ethyl acetate/ether and the solid collected. Yield 0.045 g.
TOF MS ES+375.4257 (M+1)
1H NMR: δ (DMSO-d6) 10.6(br s, 1H), 7.60-7.56(m, 2H), 7.32(dd, 1H), 7.12-7.09(m, 2H), 6.86-6.83(m, 2H), 6.49(d, 1H), 3.55-3.49(m, 3H), 2.79-2.71(m, 2H), 2.13-1.91(m, 4H), 1.56-1.46(m, 2H).
MP: 125° C.
2-Chloro-N-(3-methoxyphenyl)-acetamide (0.241 g) was added to a stirred solution of the product of Example 1 step (ii) (dihydrochloride salt) (0.4 g), triethylamine (0.608 g) in 1-methyl-2-pyrrolidinone (5 ml). The reaction mixture was heated at 80° C. for 6 h then partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried and evaporated under reduced pressure. Purification was by chromatography eluting with chloroform/isohexane/triethylamine/methanol 30:15:3:0.5. The resulting product was converted to the hydrochloride salt using ethereal hydrogenchloride. Yield 0.135 g.
TOF MS ES+422.1406 (M+1)
1H NMR: δ (DMSO-d6) 11.21(br s, 1H), 10.82(s, 1H), 9.53(br s, 2H), 7.95(s, 1H), 7.75(d, 1H), 7.60(d, 1H), 7.31-723(m, 2H), 7.15(d, 1), 6.70(dd, 1H), 4.28(br s, 2H), 3.97(br, H), 3.73(s, 3H), 2.96(br, 2H), 228-2.05(m, 4H).
MP: 274-6° C.
3,4-Dichlorophenyl isocyanate (0.081 g) was added to a stirred solution of the product from Example 1 step (ii) (0.13 g), diisopropylethylamine (0.2 g) in dichloromethane (4 ml). The reaction mixture was stirred for 20 h and the solvent removed under reduced pressure. Purification was by chromatography eluting with 5% methanol/dichloromethane. Yield 0.09 g as a solid.
TOF MS ES+446.0360 (M+1)
1H NMR: δ (DMSO-d6) 8.65(s, 1H), 7.82(d, 1H), 7.59(d, 1H), 7.54(s, 1H), 7.31 (d, 1H), 7.22(dd, 1H), 6.26(d, 1H), 3.45(br s, 3H), 2.67(m, 2H), 2.1 1(m, 2H), 1.81(m, 2H), 1.40(m, 2H).
MP: 189-190° C.
3-Methoxyphenyl isocyanate (0.064 g) was added to a stirred solution of the product from Example 1 step (ii) (0.13 g), diisopropylethylamine (0.2 g) in dichloromethane (4 ml). The reaction mixture was stirred for 20 h and the solvent removed under reduced pressure. Purification was by chromatography eluting with 5% methanol/dichloromethane. Yield 0.09 g as a solid.
MS: APCI(+ve) 408/10 (M+1)
1H NMR: δ (DMSO-d6) 8.32(s, 1H), 7.59(d, 1H), 7.55(d, 1H), 7.31(dd, 1H), 7.13(m, 1H), 7.09(d, 1H), 6.83(dd,1H), 6.47(dd, 1H), 6.09(d, 1H), 3.69(s, 3H), 3.46(m, 3H), 2.66(m, 2H), 2.13(m, 2H), 1.81(m, 2H), 1.42(m, 2H).
MP: 178-9° C.
The title compound was prepared from the product of Example 1 step (ii) (0.185 g) and 4-methoxybenzaldehyde (0.49 ul) using the method of Example 1 step (i). Yield 0.84 g as a solid.
MS: APCI(+ve) 379/81 (M+1)
1NMR: δ (DMSO-d6) 11.33(br s, 1H), 9.56(br s, 2H), 7.96 (s, 1H), 7.74(d, 1H), 7.61(d, 1H), 7.52(d, 1H), 6.97(d, 1H), 4.27(s, 2H), 4.07(s,2H), 3.77(s, 3H), 3.39-2.94(m, 5H), 2.32-2.28(m, 2H), 2.15-2.07(m, 2H).
MP: >250° C.
The following table lists Examples 108-348 which are of compounds of formula (I) all of which accord to formula (Ib).
PyBroP® (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, 2 equivalents) was added to a solution of the product from Example 1 step (ii) (hydrochloride salt, 1 mg) the appropriate acid (2 equivalents) and triethylamine in 1-methyl-2-pyrrolidone (0.2 ml) and was left for 24 h. The reaction mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0.3 ml).
Prepared following the method of Example 94 using (4-chlorophenoxy)acetic acid (0.50 g), 1,1-carbonyldiimidazole (0.50 g) and tert-butyl 4-amino-1-piperidinecarboxylate (0.46 g) to give the subtitle compound (0.54 g).
1H NMR (399.978 MHz, CDCl3) δ 134-1.40 (2H, m), 1.46 (9H, s), 1.90-1.95 (2H, m), 2.86-2.88 (2H, m), 4.01-4.14 (3H, m), 4.45 (2H, s), 638-6.41 (1H, m), 6.84-6.87 (2H, m), 726-7.30 (2H, m).
Prepared following the method of Example 1 step (ii) using tert-butyl 4-{[(4-chlorophenoxy)acetyl]amino}-1-piperidinecarboxylate (0.52 g) to give the subtitle compound (0.35 g).
1H NMR (399.978 MHz, CDCl3) δ 1.32-1.45 (2H, m), 1.93-1.97 (2H, m), 2.68-2.77 (2H, m), 3.07-3.11 (2H, m), 3.91-4.04 (1H, m), 4.45 (2H, s), 6.38-6.40 (1H, m), 6.84-6.89 (2H, m), 7.26-7.31 (2H, m).
A mixture of the product from step (ii) (1.07 mg), the appropriate alkyl halide (2 equivalents) and N,N-diisopropylethylamine (3 equivalents) in 1-methyl-2-pyrrolidinone (0.18 ml) was left at room temperature for 24 h. The mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0.4 ml).
A mixture of 2-(4-fluorophenyl)-N-(4-piperidinyl)acetamide (WO97/36871; 0.94 mg), the appropriate alkyl halide (2 equivalents) and N,N-diisopropylethylamine (3 equivalents) in 1-methyl-2-pyrrolidinone (0.18 ml) was left at room temperature for 24 h. The mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0.4 ml).
3-[3-(2-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.60 g) was dissolved in dichloromethane (10 ml). 1,1-Carbonyldiimidazole (0.33 g) was added followed by tert-butyl 4-amino-1-piperidinecarboxylate hydrochloride (0.5 g) and triethylamine (0.31 ml). After 2 hours water, brine and dichloromethane were added and the phases separated. The organic phase was dried, filtered and evaporated and the residue was purified by chromatography eluting with ethyl acetate:methanol (33:1) to give the subtitle compound (0.40 g).
1H NMR (399.98 MHz, DMSO) δ 1.22-1.24 (2H, m), 1.39 (9H, s), 1.62-1.71 (2H, m), 2.66-2.71 (4H, m), 3.18-3.23 (2H, m), 3.65-3.83 (3H, m), 7.58-7.63 (1H), 8.01-8.04 (3H, m), 8.74-8.76(1H, m).
tert-Butyl 4-({3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoyl}amino)-1-piperidinecarboxylate (0.40 g) was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (3 ml) was added. After 2 hours water, 2N sodium hydroxide and dichloromethane were added and the phases were separated. The organic phase was dried, filtered and evaporated to give the subtitle compound (0.19 g).
1H NMR (399.978 MHz, CDCl3) δ 1.35-1.45 (2H, m), 1.86-1.97 (2H, m), 2.69-2.84 (4H, m), 3.09-3.13 (2H, m), 3.32-3.36 (2H, m), 3.86-3.95 (1H, m), 5.82-5.84 (1H, m), 7.42-7.45 (1H, m), 7.83-7.87 (1H, m), 8.10-8.12 (1H, m), 8.78-8.79 (1H, m).
A mixture of the product from step (ii) (1.21 mg), the appropriate alkyl halide (2 equivalents) and N,N-diisopropylethylamine (3 equivalents) in 1-methyl-2-pyrrolidinone (0.18 ml) was left at room temperature for 24 h. The mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0.4 ml).
Prepared following the general preparation method of Examples 297-357 step (iii) using 1-(3,4-dichlorobenzyl)-4-piperidinamine hydrochloride (2.0 g), N,N-diisopropylethylamine (5.55 ml) and chloroacetyl chloride (0.55 ml) to give the subtitle compound (1.0 g).
1H NMR (399.978 MHz, CDCl3) δ 1.48-1.61 (2H, m), 1.91-1.94 (2H, m), 1.95-2.18 (2H, m), 2.77-2.80 (2H, m), 3.44 (2H, s), 3.78-3.87 (1H, m), 4.04 (2H, s), 7.13-7.16 (1H, m), 7.37-7.43 (2H, m).
A mixture of the product from step (i) (1.34 mg), the appropriate phenol (1.5 equivalents) and potassium tert-butoxide (1.4 equivalents) in 1-methyl-2-pyrrolidinone (0.13 ml) was left at room temperature for 24 hours. The mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0.4 ml).
Carbamic acid, 4-piperidinyl-, 1,1-dimethylethyl ester (6.95 g) was dissolved in N,N-dimethylformamide (70 ml). 3,4-Difluorobenzylbromide (4.55 ml) and potassium carbonate (16.0 g) were added The mixture was heated to reflux for 16 hours, then allowed to cool to room temperature. Ammonium chloride solution was added and the mixture was extracted thrice with ethyl acetate. The organic phases were washed with water (twice) and brine, then dried, filtered and evaporated. The residue was triturated with ether:iso-hexane (1:1) to give the subtitle compound (8.13 g)
1H NMR (399.978 MHz, CDCl3) δ 1.36-1.43 (m, 2H), 1.44 (s, 9H), 1.91 (d, J=11.8 Hz, 2H), 2.08 (td, J=11.4, 2.7 Hz, 2H), 2.75 (d, J=11.3 Hz, 2H), 3.41 (s, 2H), 3.42-3.55 (m, 1H), 4.38-4.47 (m, 1H), 6.96-7.02 (m, 1H), 7.04-7.11 (m, 2H), 7.13-7.19 (m, 1H)
Carbamic acid, [1-[(3,4-difluorophenyl)methyl)-4-piperidinyl]-, 1,1-dimethylethyl ester was suspended in 6N hydrochloric acid (100 ml). After 16 hours excess hydrochloric acid was evaporated and the residue azeotroped with toluene, dried and evaporated to give the subtitle compound (8.10 g).
1H NMR (399.98 MHz, DMSO) δ 1.91-2.01(2H,m), 2.31-2.47(2H,m), 2.86-3.20(2H,m), 3.54-3.66(3H,m), 4.75-4.83(2H,s), 7.26-7.61(3H,m).
1-[(3,4-Difluorophenyl)methyl]-piperidin-4-ylamine dihydrochloride (3.18 g) was dissolved in tetrahydrofuran (40 ml). Diisopropylethylamine (6.84 g) and chloroacetyl chloride (1.33 g) were added. After 3 hours water, brine and ethyl acetate were added the phase were separated. The organic phase was dried, filtered and evaporated and the residue was purified by chromatography eluting with ethyl acetate to give the subtitle compound (0.728 g).
1H NMR (CDCl3) δ 1.46-1.59 (2H, m), 1.93 (2H, dt), 2.14 (2H, td), 2.78 (2H, d), 3.43 (2H, s), 3.76-3.91 (1H, m), 4.04 (2H, s), 639-6.51 (1H, m), 6.98-7.02 (1H, m), 7.08 (1H, dd), 7.17 (1H, ddd).
The product from step (iii) (1.21 mg) was dissolved in dimethylsulfoxide (50 μl) and diisopropylethylamine (1.55 mg, 3 equivalents) was added as a solution in dimethylsulfoxide (50 μl). The appropriate thiol was added (1 equivalent) in dimethylsulfoxide (40 μl) and the reaction mixture was left at room temperature for 24 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (400 μl).
Prepared from the product of general preparation for Examples 297-340 step (iii) and the appropriate phenol following the method of Examples 280-296 step (ii).
To a solution of 1-(3,4-dichlorobenzyl)-4-piperidinamine hydrochloride (3.50 g) in to dichloromethane (100 ml) was added methyl 4-chloro-4-oxobutanoate (2.00 g) dropwise. Triethylamine (3.90 g) was added and the reaction stirred under nitrogen for 2 hours. Saturated sodium hydrogen carbonate solution was then added, with the solution being extracted three times with dichloromethane. The pooled organic phase was washed once with water, once with saturated brine and dried over anhydrous magnesium sulfate. After filtration the solvent was removed under reduced pressure to leave methyl 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (3.00 g).
MS (+veES) 373 ((M+H)+)
To a solution of methyl 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (3.72 g) in methanol (30 ml) was added lithium hydroxide (0.41 g) in water (10 ml) which was stirred under nitrogen for 48 hours. The solvent was removed under reduced pressure, the residue was triturated with ether and filtered to leave lithium 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (3.50 g).
MS (+veES) 359 ((M+H)+)
To lithium 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (0.292 g) in dichloromethane (6 ml) was added dimethylformamide (1.5 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.183 g), 1-hydroxybenzotriazole hydrate (0.130 g), 4-bromo-N′-hydroxy-1-methyl-1H-pyrazole-3-carboximidamide (0.175 g) and triethylamine (0.161 g). Reaction was left to stir for 24 hours before removal of dichloromethane under reduced pressure. Pyridine (5 ml) was added and heated at reflux for 5 hours. Pyridine was removed under reduced pressure, followed by the addition of water. The solution was extracted three times with dichloromethane. The pooled organic phase was washed once with water, once with saturated brine and dried over magnesium sulfate. After filtration the product was azeotroped twice with toluene and was purified by reverse phase hplc (RPHPLC; 75%-5%, 0.1% ammonium acetate/acetonitrile). Solvent was removed under reduced pressure to give the titled compound (0.164 g).
MS (+veAPC) 543 ((M+H)+)
1H NMR (DMSO): δ 8.21-8.17(1H,m); 7.95-7.76(1H,m); 7.60-7.54(1H,m); 7.35-7.25(1H,m); 4.35-4.21(1H,m); 3.93(2H,s); 3.44-3.35(2H,m); 3.19-3.14(3H,m); 2.73-2.64(2H,m); 2.58(3H,s); 2.00-1.89(2H,m); 1.73-1.60(2H,m); 1.36-1.24(1H,m).
To lithium 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (Example 351, step ii) (0.292 g) in dichloromethane (6 ml) was added N,N-dimethylformamide (1.5 ml), 1-(3-ethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.183 g), 1-hydroxybenzotriazole hydrate (0.130 g), N′-hydroxy-2-pyrazinecarboximidamide (0.110 g) and triethylamine (0.161 g). The reaction mixture was left to stir for 24 hours before removal of dichloromethane under reduced pressure. Pyridine (5 ml) was added and heated at reflux for 5 hours. Pyridine was removed under reduced pressure followed by the addition of water. The solution was extracted three times with dichloromethane. The pooled organic phase was washed once with water, once with saturated brine and dried over magnesium sulfate. After filtration the product was azeotroped twice with toluene and was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). Solvent was removed under reduced pressure to give the title compound (0.067 g).
MS (+veAPC) 461 ((M+H)+)
1H NMR (DMSO) δ 9.23(1H,s); 8.81-8.45(2H,m); 7.96-7.94(1H,m); 7.58-7.56(1H,m); 7.53-7.52(1H,m); 7.29-7.26(1H,m); 3.55-3.48(1H,m); 3.43(2H,s); 3.24-3.20(2H,m); 2.71-2.68(4H,m); 2.03-1.98(2H,m); 1.70-1.68(2H,m); 1.42-1.33(2H,m).
(1Z)-N′-hydroxy-2-(2-thienylsulfonyl)ethanimidamide (0.250 g) with dihydro-2,5-furandione (0.114 g) in dimethylformamide (0.2 ml) was heated at 120° C. for 2 hours. The reaction was allowed to cool and triturated with diethyl ether and filtered to leave 3-{3-[(2-thienylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}propanoic acid (0.332 g).
MS (+veES) 303 ((M+H)+)
3-{3-[(2-Thienylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}propanoic acid (0.332 g) in dichloromethane was stirred under nitrogen. Oxalyl chloride (0.252 g) was added dropwise followed by the addition of one drop of dimethylformamide. After 30 minutes the solvent and oxalyl chloride was removed under reduced pressure followed by the addition of dichloromethane (10 ml), 1-(3,4-dichlorobenzyl)-4-piperidinamine hydrochloride (0.347 g), and triethylamine (0.202 g) and allowed to stir for 2 hours under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a brown oil. This oil was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile) followed by chromatography using 3% ethanol/dichloromethane. The solvent was removed under reduced pressure, followed by the addition of hydrogen chloride in diethyl ether, filtered and dried to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-3-{3-[(2-thienylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}propanamide hydrochloride (0.04 g) as a pale yellow solid.
MS (+veES) 545 ((M+H)+)
1H NMR (DMSO) δ 10.51(1H,s); 8.21-8.13(2H,m); 7.91(1H,s); 7.77-7.71(2H,m); 7.58-7.55(1H,m); 7.28-7.26(1H,m); 5.07-5.05(2H,m); 4.26-4.25(2H,m); 3.92(1H,m); 3.34-3.31(2H,m); 3.15-3.08(2H,m); 3.02-2.94(2H,m); 2.60-2.58(2H,m); 1.92-1.84(2H,m); 1.80-1.70(2H,m).
N′-hydroxy-4-pyridinecarboximidamide (0.300 g) with dihydro-2,5-furandione (0.217 g) in dimethylformamide (2 drops) was heated for 4 times 30 seconds in a CEM MARS 5 microwave at 100% of 300 W to leave a fused mass. The reaction was allowed to cool and triturated with ethanol and filtered to leave 3-[3-(4-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.241 g).
MS (+veES) 220 ((M+H)+)
For method refer to Example 353 step ii
Purification was performed via chromatography (2.5% ethanol/dichloromehane). Solvent removed under reduced pressure to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-3-[3-(4-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide (0.154 g) as a pale cream solid.
MS (+veES) 460 ((M+H)+)
1H NMR (DMSO) δ 8.81-8.79(2H,m); 7.96-7.90(3H,m); 7.60-7.56(2H,m); 7.30-7.27(1H,m); 3.53-3.51(1H,m); 3.44(2H,s); 3.23-3.19(2H,m); 2.71-2.68(4H,m); 2.05-1.97(2H,m); 1.71-1.67(2H,m); 1.44-1.32(2H,m).
N′-hydroxy-2-pyridinecarboximidamide (0.137 g) with 3-oxabicyclo[3.1.0]hexane-2,4-dione (0.112 g) in dimethylformamide (2 drops) was heated for 4 times 30 seconds in a CEM MARS 5 microwave at 100% of 300 W to leave a fused mass. The reaction was allowed to cool and triturated with diethyl ether and filtered to leave cis-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxylic acid (0.200 g).
MS (+veES) 232 ((M+H)+)
Cis-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxylic acid (0.139 g) and
N,N′-carbonyldiimidazole (0.110 g) in dichloromethane was stirred under nitrogen for 1 hour. 1-(3,4-dichlorobenzyl)-4-piperidinamine hydrochloride (0.198 g), and triethylamine (0.121 g) was then added and allowed to stir for 24 hours under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave an oil. This oil was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). The solvent was removed under reduced pressure to leave Cis-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-[3-(2-pyridinyl)-1,2,4-oxadiazo-5-yl]cyclopropanecarboxamide (0.054 g) as a white solid.
MS (+veES) 472 ((M+H)+)
1H NMR (DMSO) δ 8.74-8.73(1H,m); 8.26-8.24(1H,m); 8.03-7.98(2H,m); 7.59-7.55(2H,m); 7.51(1H,s); 7.27-7.25(1H,m); 3.44-3.37(3H,m); 2.67-2.63(3H,m); 2.27-2.21(1H,m); 2.00-1.89(2H,m); 1.66-1.65(2H,m); 1.59-1.56(1H,m); 1.48-1.43(1H,m); 1.37-1.32(2H,m).
2-Pyridinecarbohydrazonamide (0.136 g) and dihydro-2,5-furandione (0.100 g) in 1 ml of dimethylacetamide was heated for 10 times 30 seconds in a CEM MARS 5 microwave at 100% of 300 W under nitrogen to leave 3-[3-(2-pyridinyl)-1H-1,2,4-triazol-5-yl]propanoic acid in 1 ml of dimethylacetamide.
MS (−veES) 217 ((M−H)+)
3-[3-(2-Pyridinyl)-1H-1,2,4-triazol-5-yl]propanoic acid (0.218 g in 1 ml dimethylacetamide) and N,N′-carbonyldiimidazole (0.250 g) in dichloromethane was stirred under nitrogen for 30 minutes. 1-(3,4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0.316 g), and triethylamine (0.218 g) was then added and allowed to stir for 2 hours under nitrogen. 1M sodium hydroxide was added to the reaction with the resulting solution being washed three times with dichloromethane. The aqueous phase was acidified with glacial acetic acid, with the water/acetic acid being removed under reduced pressure. Water was then added and extracted three times with dichloromethane. The pooled organic phases were extracted once with water and the water removed under reduced pressure to leave a white solid. This was then triturated with diethyl ether/dichloromethane, filtered and was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile), solvent removed to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1H-1,2,4-triazol-5-yl]propanamide (0.02 g).
MS (+veES) 459 ((M+H)+)
1H NMR (DMSO) δ 8.66-8.65(1H,m); 8.03-8.01(1H,m); 7.95-7.91(1H,m); 7.83-7.81(1H,m); 7.58-7.56(1H,m); 7.52(1H,m); 7.47-7.44(1H,m); 7.29-7.27(1H,m); 3.55-3.50(1H,m); 3.43(2H,s); 2.93-2.89(2H,m); 2.68-2.67(2H,m); 2.55-2.49(2H,m); 2.04-1.98(2H,m); 1.70-1.68(2H,m); 1.42-132(2H,m).
(3-Phenyl-1H-1,2,4-triazol-5-yl)acetic acid (0.020 g) and N,N′-carbonyl diimidazole (0.016 g) in dichloromethane was stirred under nitrogen for 30 minutes. 1-(3,4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0.031 g) and triethylamine (0.036 g) was then added and allowed to stir for 1 hour under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to a white solid. This was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). Saturated sodium hydrogen carbonate was added to the pooled collected fractions with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-(3-phenyl-1H-1,2,4-triazol-5-yl)acetamide (0.031 g).
MS (+veES) 444 ((M+H)+)
1H NMR (DMSO) δ 8.18-8.15(1H,m); 7.98-7.95(2H,m); 7.59-7.54(2H,m); 7.49-7.41(3H,m); 7.31-7.29(1H,m); 3.63(2H,s); 3.57-3.47(1H,m); 3.45(2H,s); 2.74-2.70(2H,m); 2.08-2.01(2H,m); 1.77-1.74(2H,m); 1.48-1.38(2H,m).
3-(5-Phenyl-1,3,4-oxadiazol-2-yl)propanoic acid (0.175 g) and N,N′-carbonyldiimidazole (0.148 g) in dichloromethane was stirred under nitrogen for 30 minutes. 1-(3,4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0.263 g), and triethylamine (0.126 g) was then added and allowed to stir for 2 hours under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a cream solid. This solid was purified by chromatography using 2.5% ethanol/dichloromethane. The solvent was removed under reduced pressure and was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile), followed by 1 ml of glacial acetic acid being added and the solvent removed under reduced pressure to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-(5-phenyl-1,3,4-oxadiazol-2-yl)acetamide acetate (0.024 g).
MS (+veES) 445 ((M+H)+)
1H NMR (DMSO) δ 8.31-8.29(1H,m); 7.98-7.96(2H,m); 7.66-7.54(5H,m); 7.31-7.29(1H,m); 3.92(2H,s); 3.57-3.56(1H,m); 3.46(2H,s); 2.74-2.71(2H,m); 2.07-2.02(2H,m); 1.78-1.75(2H,m); 1.47-1.39(2H,m).
2-(5-Methyl-1,2,4-oxadiazol-3-yl)pyridine (0.150 g) was stirred at −78° C. in dry tetrahydrofuran under nitrogen. (1.6M) n-butyl lithium (0.757 ml) was added dropwise so as to maintain the temperature at −78° C. After 30 minutes carbon dioxide was passed through the solution and the reaction was allowed to return to room temperature. Once the reaction had reached room temperature, water (1 ml) was added and all solvents were removed under reduced pressure to leave a yellow solid. This solid was triturated with ethyl acetate and filtered to leave a pale yellow solid (0.150 g).
1H NMR (DMSO+D2O) δ 8.75-8.73(1H,m); 8.12-8.00(2H,m); 7.65-7.61 (1H,m); 3.77(2H,s).
Lithium[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]acetate (0.140 g), 1-(3,4-dichlorobenzyl)-4-piperidinamine (0.170 g), PyBroP™ (0.400 g) were stirred under nitrogen in dimethylformamide (15 ml). N,N-Diisopropylethylamine (0.171 g) was added and left to stir for 2 hours. 1M sodium hydroxide was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave product plus dimethylformamide. Water was added which resulted in precipitation of the product. The product was filtered and was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). After removal of the solvent under reduced pressure the resulting white solid was triturated with diethyl ether, filtered and dried to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]acetamide (0.067 g).
m.p. 145° C.
MS (+veES) 446 ((M+H)+)
1H NMR (DMSO) δ 8.77-8.75(1H,m); 8.37-8.35(1H,m); 8.07-8.00(2H,m); 7.62-7.54(3H,m); 7.31-7.30(1H,m); 4.02(2H,s); 3.60-3.55(1H,m); 3.46(2H,s); 2.74-2.67(2H,m); 2.08-2.03(2H,m); 1.78-1.76(2H,m); 1.48-1.39(2H,m).
2-(4-Fluorophenyl)-N-(4-piperidinyl)acetamide (WO97/36871; 1.00 g), 1-bromo-4-(bromomethyl)benzene (1.06 g) and potassium carbonate (0.877 g) in dimethylformamide (15 ml) were heated to 70° C., under nitrogen for 1 hour. Water was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a cream solid. This solid was triturated with diethyl ether, filtered and recrystallised from ethanol/water to give white crystalline needles of N-[1-(4-bromobenzyl)-4-piperidinyl]-2-(4-fluorophenyl)acetamide.
m.p. 144° C.
MS (+veES) 407 ((M+H)+)
1H NMR (DMSO) δ 7.99-7.98(1H,m); 7.51-7.49(2H,m); 7.28-7.24(4H,m); 7.12-7.06(2H,m); 3.51-3.46(1H,n); 3.41(2H,s); 3.36(2H,s); 2.72-2.69(2H,m); 2.01-1.96(2H,m); 1.70-1.68(2H,m); 1.42-1.34(2H,m).
2-(4-Fluorophenyl)-N-(4-piperidinyl)acetamide (WO97/36871; 0.05 g), 2-quinolinecarbaldehyde (0.033 g) and sodium triacetoxyborohydride (0.067 g) in dichloroethane (3 ml) were stirred under nitrogen for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure, triturated with diethyl ether/ethyl acetate and filtered lo leave 2-(4-fluorophenyl)-N-[1-(2-quinolinylmethyl)-4-piperidinyl]acetamide (0.020 g).
MS (+veES) 378 ((M+H)+)
1H NMR (DMSO) δ 8.34-8.31(1H,m); 8.02-7.94(3H,m); 7.75-7.71(1H,m); 7.63-7.55(2H,m); 7.28-7.25(2H,m); 7.13-7.08(2H,m); 3.74(2H,s); 3.57-3.50(1H,m); 3.30(2H,s); 2.79-2.76(2H,m); 2.16-2.11(2H,m); 1.73-1.70(2H,m); 1.48-1.39(2H,m).
3-[3-(2-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.218 g) and N,N′-carbonyldiimidazole (0.194 g) were stirred in dichloromethane (10 ml) under nitrogen for 1 hour. 1-(3-Chloro-4-fluorobenzyl)-4-piperidinamine (JP 59101483; 0.242 g) was then added and left to stir for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure, triturated with ethyl acetate/ethanol and filtered to leave N-[1-(3-chloro-4-fluorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide.
m.p. 150° C.
MS (+veAPC) 444 ((M+H)+)
1H NMR (DMSO) δ 8.75-8.74(1H,m); 8.05-7.99(2H,m); 7.95-7.93(1H, m); 7.61-7.58(1H,m); 7.48-7.45(1H,m); 7.37-7.30(1H,m); 7.30-7.26(1H,m); 3.53-3.51(1H,m); 3.42(2H,s); 3.21-3.17(2H,m); 2.71-2.66(4H,m); 2.02-1.96(2H,m); 1.70-1.67(2H,m); 1.42-1.33(2H,m).
4-Chloro-3-fluorobenzaldehyde (0.793 g) and tert-butyl 4-piperidinylcarbamate (1.00 g) were stirred under nitrogen in dried tetrahydrofuran (25 ml). Sodium triacetoxyborohydride (1.266 g) was then added and left for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave tert-butyl 1-(4-chloro-3-fluorobenzyl)-4-piperidinylcarbamate (1.80 g) as a white solid.
MS (+veAPC) 343 ((M+H)+)
tert-Butyl 1-(4-chloro-3-fluorobenzyl)-4-piperidinylcarbamate (1.80 g) in dichloromethane (20 ml) was stirred under nitrogen. Trifluoroacetic acid (5 ml) was then added dropwise and the reaction was left to stir for 2 hours. 1M sodium hydroxide was added to the reaction until basic, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. Product purified by chromatography (5% ethanol/dichloromethane to 10% ethanol/dichloromethane) and solvent runoved under reduced pressure to leave an oil which crystallised over the period of 48 hours. The resulting solid was triturated with diethyl ether and filtered to leave 1-(4-chloro-3-fluorobenzyl)-4-piperidinamine (0.500 g) as a white solid.
3-[3-(2-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.136 g) and N,N′-carbonyldiimidazole (0.114 g) were stirred in dichloromethane (10 ml) under nitrogen for 1 hour. 1-(4-Chloro-3-fluorobenzyl)-4-piperidinamine (0.150 g) was then added and left to stir for 2 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave an oil. This was triturated with diethyl ether which caused product the to crystallise. After filtration, the product was washed with diethyl ether and dried to N-[1-(4-chloro-3-fluorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide.
m.p. 132° C.
MS (+veES) 444 ((M+H)+)
1H NMR (DMSO) δ 8.76-8.74(1H,m); 8.05-7.99(2H,m); 7.95-7.94(1H,m); 7.61-7.58(1H,m); 7.54-7.50(1H,m); 7.32-7.28(1H,m); 7.16-7.14(1H,m); 3.55-3.47(1H,m); 3.44(2H,s); 3.21-3.17(2H,m); 2.71-2.66(4H,m); 2.03-1.97(2H,m); 1.70-1.67(2H,m); 1.42-1.33(2H,m).
The product from Example 1 step (ii) was dissolved in dichloromethane (10 ml) containing triethylamine (0.081 g) and the solution was cooled to 0° C. 4-Chlorophenoxyacetyl chloride (88 mg) in dichloromethane (3 ml) was added dropwise, the cooling bath was removed and the resulting solution was stirred for 1 hour. Ethyl acetate, water and brine were added and the phases were separated. The organic phase was dried, filtered and evaporated to give an oil which was purified by reverse phase HPLC (with a gradient eluent system (25% MeCN/NH4OAcaq (0.1%) to 95% MeCN/NH4OAcaq (0.1%)) to give the title compound (0.049 g).
1H NMR: (CDCl3): δ]1.51 (2H, ddd), 1.89-1.96 (2H, m), 2.15 (2H, td), 2.77 (2H, d), 3.43 (2H, s), 3.85-3.96 (1H, m), 4.44 (2H, s), 6.37 (1H, d), 6.85 (2H, dt), 7.14 (1H, dd), 7.26-7.29 (2H, m), 7.37 (1H, d), 7.43 (1H, d)
To a solution of 3-(3-Pyridin-2-yl-[1,2,4]oxadiazol-5-yl)-propionic acid (1 g) in tetrahydrofuran (5 ml), was added carbonyldiimidazole (0.74 g). The mixture was stirred for 10 minutes before addition of 1-benzyl-piperidin-4-ylamine (1 ml) in tetrahydrofuran (5 ml). The reaction mixture was stirred for 15 minutes then partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, dried (MgSO4) and solvent removed by evaporation. Purification by Biotage® 40S eluting 3% MeOH/0.5% 880 ammonia/dichloromethane gave the title compound (0.93 g).
MS: ESI 392 (+H)
1H NMR: (CDCl3): δ 1.44 (2H, ddd), 1.88 (2H, d), 2.10 (2H, t), 2.73-2.78 (2H, m), 2.80 (2H, t), 3.33 (2H, t), 3.46 (2H, s), 3.75-3.86 (1H, m), 5.57 (1H, d), 7.23-7.32 (5H, m), 7.42 (1H, ddt), 7.84 (1H, tt), 8.10 (1H, dd), 8.79 (1H, td).
To a solution of (2-amino-ethyl)-carbamic acid-tert-butyl ester (5 g) and triethylamine (6.5 ml) in tetrahydrofuran (1000 ml) at 0° C. was added methyliodide (1.94 ml) dropwise over a period of 1 hour. The mixture was allowed to warm to ambient temperature and stirred for 72 hours before removal of solvents by evaporation. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4) and solvent removed by evaporation to give the title compound (3.7 g).
MS: ESI 57((CH3)4C+), 118 (M+H—(CH3)4C)
To a solution of dichlorobenzyl-piperidin-4-one (Example 74, step (i), 4.8 g) and acetic acid (1 ml) in dichloromethane (100 ml) was added (2-methylamino-ethyl)-carbamic acid tert-butyl ester (3.26 g) and the mixture was stirred for 5 minutes before addition of sodium triacetoxyborohydride (7.9 g). The reaction mixture was stirred for 12 hours before addition of sodium bicarbonate solution. The mixture was stirred for ½ hour and then partitioned between water and dichloromethane. The organic layer was separated, dried (MgSO4) and solvent removed by evaporation. Purification by Biotage® 40S eluting 10% MeOH/2% triethylaniine/dichloromethane gave the title compound (1.7 g).
MS: ESI 316/318 (+H—(CH3)4COCO)
1H NMR: (CDCl3): δ 1.44 (9H, s), 1.50-1.60 (4H, m), 1.65-1.72 (2H, m), 1.95 (2H, td), 2.23 (3H, s), 2.34 (1H, tt), 2.88 (2H, d), 3.14-3.20 (2H, m), 3.41 (2H, s), 4.95-5.01 (1H, m), 7.13-7.15 (1H, m), 7.37 (1H, d), 7.42 (1H, d).
(2-{[1-(3,4-Dichloro-benzyl)-piperidin-4-yl]-methyl-amino}-ethyl)-carbamic acid tert-butyl ester (1.7 g) was dissolved in 6M HCl (20 ml) and stirred for 12 hours. The solvent was evaporated and the residue was azeotroped with toluene and then sodium bicarbonate solution was added. The mixture was stirred for 10 minutes and the product was extracted with dichloromethane. The solvent was removed by evaporation to give the title compound (0.75 g).
MS: ESI 316/318 (+H)
Prepared by the method of Example 359 step (ii) using N1-[1-(3,4-Dichloro-benzyl)-piperidin-4-yl]-N1-methyl-ethane-1,2-diamine and 2-fluorophenylacetic acid.
MS: ESI 452/454 (+H)
1H NMR: (CDCl3): δ 2.08-1.94 (2H, m), 2.37-2.33 (2H, m), 2.95 (3H, s), 3.18 (2H, t), 3.41 (2H, m),3.66-3.78(4H, m), 3.75 (2H, s), 3.84 (1H, m), 4.38 (2H, s), 7.16-7.28 (2H, m), 7.36-7.42 (2H, m), 7.45 (1H, dd), 7.73 (1H, d), 7.72 (1H, d).
To a solution of 1-(3,4-Dichlorobenzyl)-piperidin-4-one (3.1 g) in dichloromethane (50 ml) and acetic acid (0.69 ml) was added methylamine (6 ml of a 1M solution in tetrahydrofuran). The mixture was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (3 g) and the resulting mixture stirred for 72 hours. Sodium bicarbonate solution (100 ml) added and the mixture stirred vigorously for 5 minutes before extraction of the product with dichloromethane (2×200 ml). The organics were separated, bulked and dried, (MgSO4). Purification by Biotage® 40S eluting 10% MeOH/0.5% 880 ammonia/dichloromethane gave the sub-title compound (1.8 g).
MS: ESI 273/275 (+H)
1H NMR: (CDCl3): δ 1.36 (2H, qd), 1.82-1.91 (2H, m), 2.03 (2H, td), 2.36 (1H, tt), 2.43 (3H, s), 2.76-2.83 (2H, m), 3.43 (2H, s), 7.15 (1H, dd), 737 (1H, d), 7.42 (1H, d).
To a solution of 4-fluorophenylacetic acid (100 mg) in tetrahydrofuran (3 ml) was added carbonyldiimidazole (105 mg). The mixture was stirred for 10 minutes before addition of [1-(3,4-dichlorobenzyl)-piperidin-4-yl]-methyl-amine (177 mg) in tetrahydrofuran (2 ml). Stirring was continued for 1 hour then solvent removed by evaporation. Purification by Biotage® 40S eluting 2% MeOH/0.5% 880 ammnonia/dichloromethane gave the title compound (166 mg).
MS: ESI 273/275 (M+H)
1H NMR: (CDCl3) δ 1.57 (1H, d), 1.69 (1H, qd), 1.76-1.84 (1H, m), 1.88 (1H, q), 2.10 (2H, td), 2.85-2.90.(1H, m), 2.85 (3H, s), 3.42 (2H, s), 3.58 (1H, tt), 3.67 (2H, s), 4.51 (1H, tt), 7.00 (2H, t), 7.11-7.15 (1H, m), 7.18-7.23 (2H, m), 7.37 (1H, d), 7.41 (1H, dd).
Ethyl glycolate (1.04 g) was dissolved in tetrahydrofuran (10 ml) and the solution was cooled to 0° C. Sodium hydride (60% suspension in oil, 0.43 g) was added and the suspension was stirred and then sonicated in an ultrasonic bath. 2-Chloropyrimidine (1.14 g) was added and the mixture was sonicated for a further 110 min. Ammonium chloride solution was added and the mixture was extracted thrice with ethyl acetate, the organic phases were washed with brine and dried, filtered and evaporated. The residue was purified by chromatography eluting with iso-hexane:ethyl acetate (13:7) to give the subtitle compound (1.40 g) as an oil.
1H NMR (299.944 MHz, CDCl3) δ 1.26 (t, J=6.8 Hz, 3H), 4.24 (q, J=7.1 Hz, 2H), 4.93 (s, 2H), 6.98 (t, J=4.8 Hz, 1H), 8.53 (d, J=4.8 Hz, 2H).
Ethyl 2-pyrimidinyloxyacetate (1.4 g) was dissolved in ethanol (10 ml). Sodium hydroxide (2M aq) was added and the mixture was stirred for 64 h. The solvent was evaporated and the reside was dissolved in water, filtered and the acidified with concentrated hydrochloric acid. The resulting precipitate was collected and dried to give the subtitle compound (0.698 g).
1H NMR (399.98 MHz, DMSO) δ 4.85 (s, 2H), 7.09 (t, J=4.9 Hz, 1H), 8.56 (d, J=4.8 Hz, 2H).
The title compound was prepared from the product of Example 1 step (ii) (hydrochloride salt, 335 mg) and 2-pyrimidinyloxyacetic acid (170 mg) using the method of Example 94.
Yield 140 mg.
m.p. 120-122° C.
IH NMR (399.978 MHz, CDCl3) δ 1.50 (q, J=11.6 Hz, 2H), 1.91 (d, J=11.9 Hz, 2H), 2.13 (t, J=11.1 Hz, 2H), 2.77 (d, J=11.4 Hz, 2H), 3.42 (s, 2H), 3.86-3.95 (m, 1H), 4.87 (s, 2H), 6.49 (d, J=6.9 Hz, 1H), 7.05 (t, J=4.9 Hz, 1H), 7.14 (m, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.42 (s, 1H), 8.57 (d, J=4.8 Hz, 2H).
2,5-Dimethoxytetrahydrofuran (4.92 g) was stirred in hydrochloric acid (1M, 25 ml) for 1 hour. 3,4-Dichlorobenzylamine (5 ml) was added to hydrochloric acid (1M, 15 ml) and the resulting suspension was added to the first solution. Phosphate buffer solution (pH 5.5, 250 ml) was added followed by sodium hydroxide (1.6 g). A solution of acetone dicarboxylic acid (4.77 g) in phosphate buffer solution (pH 5.5, 90 ml) was added to the mixture and the solution was stirred. A yellow solid formed and the mixture was left to stand for 64 h. The aqueous supernatant was decanted and hydrochloric acid (2.5M) was added to the solid along with ethyl acetate. The layers were separated and the aqueous phase was extracted twice with dichloromethane containing a little methanol. The organic layers were combined and evaporated to give a crude oil (ca 7 g). A portion of the product (ca 2.5 g) was purified by chromatography eluting with dichloromethane:methanol (19:1) to give the subtitle compound (1.62 g) as a yellow oil.
1H NMR (299.944 MHz, CDCl3) δ 1.62-1.70 (m, 2H), 2.09-2.15 (m, 2H), 2.23 (d, J=15.9 Hz, 2H), 2.67 (d, J=16.7 Hz, 2H), 3.43-3.49 (m, 2H), 3.68 (s, 2H), 7.26 (d, J=8.7 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.54 (s, 1H)
8-[(3,4-Dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-one (751 mg) and carbamic acid, (2-aminoethyl)-1,1-dimethylethyl ester (520 mg) were dissolved in dichloroethane (23 ml). Sodium triacetoxyborohydride (697 mg) was added and the suspension was stirred at room temperature for 20 hours. Dichloromethane was added and the solution was to washed with sodium bicarbonate solution, then with water and then with brine. Chromatography of the residue eluting with ethyl acetate:methanol:triethylamine (80:19:1) gave the subtitle compound (688 mg) as an oil.
1H NMR (399.978 MHz, CDCl3) δ 1.45 (s, 9H), 1.52 (d, J=14.4 Hz, 2H), 1.96-2.09 (m, 6H), 2.67 (t, J=5.8 Hz, 2H), 2.88 (t, J=6.4 Hz, 1H), 3.08-3.12 (m, 2H), 3.21 (q, J=5.7 Hz, 2H), 3.48 (s, 2H), 4.80-4.95 (m, 1H), 7.22 (dd, J=8.3, 2.0 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H)
Carbamic acid, [2-[[8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]amino]ethyl]-, 1,1-dimethylethyl ester (337 mg) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (3 ml) was added. The resulting solution was stirred for 1 hour then the volatiles were evaporated. The residue was dissolved in dichloromethane (3 ml) and triethylamine (1 ml) was added followed by 3-methoxybenzoyl chloride (120 μl). The solution was stirred overnight. The solvent was evaporated and the residue was purified by RPHPLC (gradient ammonium acetate 1% aqueous: acetonitrile (25% acetonitrile to 95% acetonitrile)). Excess tosic acid in ether was added to the residue and the resultant salt was recystallised from a mixture of ethyl acetate—ethanol with a little cyclohexane to give the title compound (77 mg).
m.p. 180-182.5° C.
1H NMR (399.98 MHz, DMSO) δ 2.10-2.24 (m, 4H), 2.29 (s, 6H), 2.39-2.47 (m, 4H), 3.21-3.28 (m, 2H), 3.52-3.57 (m, 1H), 3.57-3.63 (m, 2H), 3.80 (s, 3H), 3.85-3.91 (m, 2H), 4.21 (d, J=5.4 Hz, 2H), 7.11 (d, J=9.4 Hz, 4H), 7.13-7.18 (m, 1H), 7.38-7.45 (m, 3H), 7.48 (d, J=7.9 Hz, 4H), 7.56 (d, J=6.7 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.84-7.90 (m, 1H), 8.38-8.52 (m, 2H), 8.81-8.87 (m, 1H), 9.44-9.51 (m, 1H).
8-[(3,4-Dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-one (350 mg) was dissolved in dry methanol (12 ml) and ammonium acetate (1 g) was added. The mixture was stirred to get partial solution and then sodium cyanoborohydride (106 mg) was added. The mixture was heated under reflux for 150 minutes, then allowed to cool to room temperature. The methanol was evaporated, the residue was partitioned between sodium hydroxide and dichloromethane, and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried, filtered and evaporated to give the subtitle compound.
[M+H]+ (ES+) 285
3-(2-Pyridinyl)-1,2,4-oxadiazole-5-propanoic acid (305 mg) was suspended in dichloromethane (6 ml) and oxalyl chloride (0.5 ml) was added. The mixture was stirred overnight. Toluene (1 ml) was added to the solution, the volatiles were evaporated, then the residue was redissolved in dichloromethane (2 ml). Endo-8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-amine (all from step(i)) was dissolved in dichloromethane (4 ml) containing triethylamine (0.5 ml) and then cooled in an ice bath. The acid chloride solution was added to the amine and the mixture was stirred for 1 hour. Water was added to the reaction mixture and the phases were separated. The aqueous phase was extracted twice with dichloromethane, the organic phases were dried, filtered and evaporated. The residue was purified by RPHPLC (gradient ammonium acetate 1% aqueous:acetonitrile (25% acetonitrile to 95% acetonitrile)). The product was suspended in ether and the ethereal hydrochloric acid was added, the suspension was stirred and then the diethyl ether was evaporated. The residue was dissolved in hot ethyl acetate containing ethanol and crystallisation was induced by adding iso-hexane to give the title compound (47 mg).
1H NMR (399.98 MHz, DMSO) δ 1.99-1.90 (m, 2H), 2.41-2.20 (m, 6H), 2.77 (t, J=6.8 Hz, 2H), 3.23 (t, J=6.9 Hz, 2H), 3.81-3.72(m, 3H), 4.15 (d, J=6.2 Hz, 2H), 7.63-7.58 (m, 1H), 7.67 (dd, J=7.6, 2.3 Hz, 2H), 7.76 (d, J=9.3 Hz, 1H), 8.06-7.99 (m, 3H), 8.11 (d, J=4.1 Hz, 1H), 8.75 (d, J=4.6 Hz, 1H), 10.13 (t, J=5.6 Hz, 1H).
4-Acetaminophenol (1.51 g), potassium carbonate (1.38 g) and methyl bromoacetate (1.0 ml) were combined in acetone (40 ml) and heated to reflux for 5 hours. The mixture was allowed to cool to room temperature, filtered and evaporated. The residue was dissolved in ethyl acetate, washed with water and then with brine then dried, filtered and evaporated to give the subtitle compound (232 g).
1H NMR (399.978 MHz, CDCl3) δ 2.16 (s, 3H), 3.80 (s, 3H), 4.62 (s, 2H), 6.87 (d, J=9.1 Hz, 2H), 7.07 (br s, 1H), 7.40 (d, J=9.0 Hz, 2H)
Methyl(4-acetaminophenoxy)acetate was hydrolysed following the method of Example 368 step (ii) to give the subtitle compound (1.85 g).
1H NMR (399.98 MHz, DMSO) δ 2.00 (s, 3H), 4.61 (s, 2H), 6.84 (d, J=9.0 Hz, 2H), 7.46 (d, J=9.0 Hz, 2H), 9.80.(s, 1H).
The title compound was prepared from the product of Example 1 step (ii) (free base, 281 mg) and (4-acetaminophenoxy)acetic acid (229 mg) using a method hereinbefore described (yield 40 mg).
m.p. 177-178.5° C.
1H NMR (299.946 MHz, DMSO) δ 1.51 (qd, J=10.5, 3.7 Hz, 2H), 1.72-1.63 (m, 2H), 2.00 (s, 3H), 2.05 (t, J=3.7 Hz, 2H), 2.77-2.68 (m, 2H), 3.45 (s, 2H), 3.70-3.57 (m, 1H), 4.39 (s, 2H), 6.88 (d, J=9.0 Hz, 2H), 7.29 (dd, J=8.1, 1.7 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.54 (d, J=1.5 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 9.79 (s, 1H).
The title compound was prepared from the product of Example 1 step (ii) (free base, 172 mg) and 4-hydroxyphenylacetic acid (135 mg) using a method hereinbefore described (yield 57 mg).
m.p. 72-97° C.
1H NMR (399.98 MHz, DMSO) δ 1.37 (q, J=7.0 Hz, 2H), 1.69 (d, J=11.3 Hz, 2H), 2.02 (t, J=5.3 Hz, 2H), 2.71 (d, J=11.3 Hz, 2H), 3.23 (s, 2H), 3.44 (s, 2H), 3.55-3.42 (m, 1H), 6.66 (d, J=8.5 Hz, 2H), 7.02 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.2 Hz, 1H), 7.53 (s, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 9.18 (s, 1H).
8-[(3,4-Dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-one (330 mg) was dissolved in tetrahydrofuran (5 ml) and cooled to 0° C. Lithium tris(3-ethylpentyl-3-oxy)aluminohydride solution (0.5M, 2.5 ml) was added dropwise and the mixture was allowed to attain room temperature overnight. Sodium sulfite decahydrate (ca 2 g) was added and the suspension was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, filtered through kieselguhr and evaporated. The residue was purified by chromatography eluting with dichloromethane:methanol (9:1) to give the subtitle compound 161 mg.
1H NMR (399.978 MHz, CDCl3) δ 1.59 (d, J=8.1 Hz, 2H), 1.64 (t, J=11.4 Hz, 2H), 1.86-1.81 (m, 2H), 2.00-1.97 (m, 2H), 3.21-3.18 (m, 2H), 3.55 (s, 2H), 3.95 (septet, J=5.6 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.37 (d, J=7.4 Hz, 1H), 7.50 (s, 1H).
Endo-8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-ol (556 mg), phthalimide (321 mg) and polymer bound triphenylphosphine (821 mg) were combined in tetrahydrofuran (10 ml). Diethylazodicaboxylate (330 μl) was added and the mixture was stirred gently overnight Additional phosphine (0.5 g) and diethylazodicaboxylate (200 μl) were added and the mixture was stirred for an additional 5 days. The reaction mixture was diluted with ethyl acetate and filtered; the residue was washed with ethyl acetate and methanol. The filtrate was evaporated, and chromatographed eluting with 9:1 ethyl acetate:methanol. RPHPLC of the product (gradient ammonium acetate 1% aqueous: acetonitrile (25% acetonitrile to 100% acetonitrile)) gave the subtitle compound (90 mg).
1H NMR (399.978 MHz, CDCl3) δ 1.47-1.39 (m, 2H), 1.78 (d, J=7.7 Hz, 2H), 2.14-2.02 (m, 2H), 2.64 (t, J=11.8 Hz, 2H), 3.36-3.25 (m, 2H), 3.92-3.81 (m, 2H), 4.56 (septet, J=6.1 Hz, 1H), 7.41-7.32 (m, 2H), 7.59-7.55 (m, 1H), 7.74-7.69 (m, 2H), 7.86-7.82 (m, 2H).
Exo-2-[8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]-1H-isoindole-1,3(2H)-dione (90 mg) was dissolved in ethanol (6 ml) containing dichloromethane (3 ml); hydrazine hydrate (0.2 ml) was added and the resulting solution was stirred at room temperature for 26 hours. The suspension was filtered and the filtrate was evaporated to give the subtitle compound (55 mg).
1H NMR (399.978 MHz, CDCl3) δ 1.51-1.43 (m, 2H), 1.59 (q, J=4.9 Hz, 2H), 1.75-1.67 (m, 2H), 2.00-1.94 (m, 2H), 3.02-2.92 (m, 1H), 3.18-3.12 (m, 2H), 3.50 (s, 3H), 7.21 (d, J=8.2 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.50 (s, 1H).
Prepared following the method of Example 370 step (iii) but without salt formation to give the title compound (15 mg).
m.p. 177.5-178° C.
1H NMR (299.946 MHz, DMSO): δ 1.63-1.43 (m, 6H), 1.99-1.90 (m, 2H), 2.64 (t, J=7.1 Hz, 2H), 3.11-3.06 (m, 2H), 3.18 (t, J=6.2 Hz, 2H), 3.49 (s, 2H), 3.97-3.83 (m, 1H), 7.32 (dd, J=8.3, 1.9 Hz, 1H), 7.62-7.56 (m, 3H), 7.87 (d, J=8.1 Hz, 1H), 8.06-7.97 (m, 2H), 8.75 (dt, J=3.7, 0.8 Hz, 1H).
(R)-(4-Bromophenyl)ethylamine (1.01 g) and potassium carbonate (1.45 g) were dissolved in a mixture of ethanol (13 ml) and water (6 ml) and then heated to a vigorous reflex. A solution of 4-hydroxy-4-methoxy-1,1-dimethyl-piperidinium iodide (J. Chem. Soc. Perkin Trans. 2, (1984) 1647) (1.47 g) in warm water (6 ml) was added dropwise over 40 minutes; reflux was maintained for a further 12 hours, then the reaction was allowed to cool to room temperature. The mixture was evaporated and ethyl acetate and water were added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate, the organic layer was washed with brine, dried, filtered and evaporated. Chromatography of the residue eluting with iso-hexane:ethyl acetate (3:2) gave the subtitle compound (804 mg).
1H NMR (399.978 MHz, CDCl3) δ 2.66-2.80 (m, 4H), 1.38 (d, J=6.9 Hz, 3H), 2.42 (t, J=6.2 Hz, 4H), 3.58 (q, J=6.7 Hz, 1H), 7.24 (d, J=8.5 Hz, 2H), 7.46 (d, J=9.0 Hz, 4H).
Prepared following the general method of Example 370 step (i) (R)-1-[1-(4-bromophenyl)ethyl]-4-piperidinone (420 mg) ammonium acetate (0.80 g) and sodium cyanoborohydride (120 mg) to give the subtitle compound (449 mg).
1H NMR (399.978 MHz, CDCl3) δ 1.33 (d, J=6.9 Hz, 3H), 1.43-1.26 (m, 2H), 1.73 (d, J=12.3 Hz, 1H), 1.81 (d, J=12.6 Hz, 1H), 2.03-1.90 (m, 2H), 2.60 (tt, J=10.6, 5.1 Hz, 1H), 2.71 (d, J=13.6 Hz, 1H), 2.94 (d, J=11.3 Hz, 1H), 3.37 (q, J=6.7 Hz, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H)
Prepared following a method as hereinbefore described using (R)-1-[1-(4-bromophenyl)ethyl]-4-piperidinamine (449 mg), 3-(2-pyridinyl)-1,2,4-oxadiazole-5-propanoic acid (0.3 1 g), 1-hydroxybenzotriazole (0.20 g), 4-(N,N-dimethylamino)-pyridine (0.13 g) and 1-ethyl-3-[3-dimethylamino)-propyl]carbodiimide hydrochloride (0.30 g) to give the title compound (40 mg).
m.p. 153-155° C.
1H NMR (399.98 MHz, DMSO) δ 1.23 (d, J=6.7 Hz, 3H), 1.40-1.26 (m, 2H), 1.66-1.61 (m, 1H), 1.73-1.67 (m, 1H), 1.97-1.86 (m, 2H), 2.64-2.59 (m, 1H), 2.66 (t, J=7.2 Hz, 2H), 2.84-2.79 (m, 1H), 3.18 (t, J=7.2 Hz, 2H), 3.42 (q, J=6.4 Hz, 1H), 3.48-3.39 (m, 1H), 7.25 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.5 Hz, 2H), 7.59 (ddd, J=6.7, 4.6, 2.1 Hz, 1H), 7.91 (d, J=7.4 Hz, 1H), 8.04-7.99 (m, 2H), 8.75 (dt, J=4.4, 1.4 Hz, 1H).
Prepared following an analogous series of steps to example 374 but using (S)-(4-bromophenyl)ethylamine to give the title compound.
m.p. 141.5-143° C.
αD 29.55° (c=0.13, methanol 21° C.)
1H NMR (299.946 MHz, DMSO) δ 1.23 (d, J=6.7 Hz, 3H), 1.26-1.41 (m, 2H), 1.64 (t, J=8.1 Hz, 2H), 1.92 (q, J=11.2 Hz, 2H), 2.58-2.67 (m, 1H), 2.67 (t, J=7.2 Hz, 2H), 2.78-2.85 (m, 1H), 3.18 (t, J=7.1 Hz, 2H), 3.37-3.46 (m, 1H), 3.42 (q, J=6.7 Hz, 1H), 7.25 (d, J=6.7 Hz, 2H), 7.49 (d, J=8.5 Hz, 2H), 7.57-7.62 (m, 1H), 7.91 (d, J=7.7 Hz, 1), 7.98-8.05 (m, 2H), 8.75 (d, J=7.5 Hz, 1H).
The title compound was prepared from 1-(3,4-dichlorobenzyl)piperidine-4-amine (free base 187 mg), 3-(3-pyridinyl)propanal (125 mg), sodium triacetoxyborohydride (70 mg), and 0.02 ml acetic acid, stirred together for 2 hrs in dichloromethane (10 ml). Water was added, the mixture neutralised with sodium bicarbonate and the organic phase separate, dried and chromatographed on silica with ethyl acetate/methanol (9:1) as eluant, to give the title compound (70 mg) as a colourless oil.
MS [M+H]+ (ES+) 378
1H NMR: (CDCl3) δ 1.36-1.40 (2H, m), 1.75-1.85 (4H m), 2.0 (2H, t), 2.1-2.2 (2H, m), 2.4-2.45 (1H m), 2.6-2.7 (3H, m), 2.75-2.79 (2H, m), 3.4 (2H, s), 7.1-7.54 (5H, d), 8.44 (2H, m).
MS [M+H]+ (ES+) 469
1H NMR: (CDCl3) δ 1.46-1.50 (2H, m), 1.7-1.8 (2H, m), 2.0-2.1 (2H, m), 2.5-2.6 (2H, m), 3.45 (2H, s), 3.65-3.7 (1H, m), 4.5 (2H, s), 7.25-7.3 (2H, m), 7.27-7.63 (9H, m), 8.0 (1H, d).
MS [M+H]+ (ES+) 403
1H NMR: (CDCl3) δ 1.46-1.40 (2H, m), 1.85-1.95 (2H, d), 2.05-2.15 (2H, t), 2.75-2.79 (2H, d), 3.1 (2H, d), 3.4 (2H, s), 3.85-3.95 (1H, m), 5.45 (1H, m), 6.3 (1H, m), 6.5 (1H, d), 7.07-7.43 (8H, m).
MS [M+H]+ (ES+) 419
1H NMR: (CDCl3) δ 1.46-1.50 (2H, m), 2.0 (2H, m), 2.15-2.25 (2H, m), 2.75-2.85 (2H, m), 3.4 (2H, s), 3.8 (3H, s), 3.94-4.05 (1H, m), 5.5 (1H, d), 6.35-6.4 (1H, d), 6.9-7.5 (7H, m), 7.6 (1H, d).
MS [M+H]+ (ES+) 533
1H NMR: (CDCl3) δ 1.46-1.50 (2H, m), 1.9 (2H, d), 2.1-2.2 (2H, t), 2.6 (2H, m), 2.75-2.85 (2H, d), 3.4 (2H, d), 3.8-3.9 (1H, m), 4.20 (2H, m), 6.65-6.7 (2H m), 7.1-7.2 (1H, d), 7.35-7.45 (2H, m), 7.54-7.6 (2H, m).
MS [M+H]+ (ES+) 464
1H NMR: (CDCl3) δ 1.4 (2H, m), 1.6-1.65 (2H, m), 2.05 (2H, m), 2.45 (2H, m), 2.65-2.75 (2H, m), 3.0 (2H, m) 3.45 (2H, s), 3.5 (1H, m), 3.7 (3H, s), 5.9 (1H, m), 6.85 (2H, d), 7.3-7.6 (4H, m), 7.7 (1H, d), 9.7 (1H, s).
MS [M+H]+ (ES+) 471
1H NMR: (CDCl3) δ 1.46-1.50 (2H, m), 1.9-2.0 (2H, m), 2.0-2.1 (2H, m), 2.75-2.85 (2H, m), 3.4 (2H, s), 3.9-4.0 (1H, m), 4.92 (2H, s), 6.53 (1H, d), 7.1-7.6 (7H, m), 7.7 (1H, s), 8.76 (2H, s).
MS [M+H]+ (ES+) 545
1H NMR: (CDCl3) δ 1.46-1.50 (2H, m), 1.8 (2H, m), 2.1-2.2 (2H, t), 2.65 (2H, m), 3.4 (2H, s), 3.9(3H, m), 6.8 (1H, d), 7.0 (2H, m), 7.5-7.7 (7H, m), 8.8 (2H, d).
MS [M+H]+ (ES+) 412
1H NMR: (CDCl3) δ 1.46-1.50 (2H, m), 1.8 (2H, m), 2.1 (2H, m), 2.65 (2H, m), 3.4 (2H, s), 3.8 (3H, m), 6.90 (1H m), 7.05-7.2 (4H, m), 8.58 (2H, d).
MS [M+H]+ (ES+) 491
1H NMR: (CDCl3) δ 1.46-1.50 (2H, m), 1.8 (2H, m), 2.15 (2H, m), 2.6 (2H, m), 3.4 (2H, s), 3.8 (3H, m), 6.6 (1H, d), 7.1 (1H m), 7.3-7.4 (2H, m) 8.58 (2H, d).
MS [M+H]+ (ES+) 378
1H NMR: (CDCl3) δ 1.36-1.40 (2H, m), 1.8 (2H, m), 2.05 (2H m), 2.65 (2H, m), 3.4 (2H,m), 3.67 (2H, s), 3.8 (1H, m), 6.5 (1H, m), 6.9-7.24 (4H, m) 8.48 (2H, d).
MS [M+H]+ (ES+) 454
1H NMR: (CDCl3) δ 1.36-1.40 (2H, m), 1.87 (2H, m), 2.05 (2H m), 2.5 (2H, m), 2.65 (2H, m), 2.96 (2H, m), 3.4 (2H, s), 3.8 (1H, m), 5.35 (1H, d), 5.95-6.0 (1H, m) 6.38 (1H, m), 7.1-7.5 (8H, m), 9.5 (1H m).
The title compound (20 mg) was prepared by heating at reflux N1-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-1,2-ethanediamine (100 mg) and 2-chloro-5-phenypyrimidine (100 mg) and Hunigs' base (10 mg) in toluene for 8 hours. The mixture was purified by chromatography on silica, with ethyl acetate methanol (9:1) as eluant to give the title compound as a yellow oil.
MS [M+H]+ (ES+) 456/8
1H NMR: (CDCl3) δ 1.51 (2H, m), 1.75 (2H, m), 2.15 (2H, td), 2.9 (2H, m), 3.05 (1H, m), 3.15 (2H, m), 3.44 (2H, m), 3.8 (2H, m), 6.65 (1H, m), 7.0-7.4 (8H, m), 8.5 (2H, m).
Prepared by the method of Example 397 amine (200 mg), 2-chloro-5-bromopyrimidine (130 mg), Hunigs' base (200 mg) to give the title compound (20 mg).
MS [M+H]+ (ES+) 458/60
1H NMR: (CDCl3) δ 1.4 (2H, m), 1.75 (2H, m), 2.05 (2H, td), 2.85 (2H, m), 3.0 (1H, m), 3.15 (2H, m), 3.44 (2H, m), 3.75 (2H, m), 6.8 (1H, m), 7.0-7.4 (3H, m), 8.25 (2H, m).
MS [M+H]+ (ES+) 430/32
1H NMR: (CDCl3) δ 1.40-1.45 (2H, m), 1.97 (2H, m), 2.15 (2H m), 2.75 (2H, d), 3.4 (2H, s), 3.8 (1H, m), 4.05 (2H, d), 5.75 (1H, d), 5.84 (1H m), 6.38 (1H, d), 7.1-7.15 (1H d), 7.36-7.42(2H m), 8.0 (1H d).
MS [M+H]+ (ES+) 475
1H NMR: (CDCl3) δ 1.46-1.50 (2H, m), 1.87 (2H, m), 2.15 (2H, m), 2.75 (2H, m), 3.4 (2H, s), 3.9 (1H, m) 4.8 (2H, s), 6.38 (1H, d), 7.1-7.15 (1H m), 7.4 (2H, m), 8.6 (2H, s).
MS [M+H]+ (ES+) 446
1H NMR: (CDCl3) δ 1.46-1.50 (2H, m), 1.87 (2H, m), 2.15 (2H m), 2.75 (2H, m), 3.4 (2H, s), 3.8 (1H, m), 4.3 (2H s), 5.65 (1H, m), 7.1-7.36 (3H, m) 7.38-7.78 (2H, m), 7.87-7.95 (2H, m).
1H NMR: (CDCl3) (of the free base): δ 1.4 (2H, m) 1.85 (2H, m), 2.05 (2H, m) 2.55 (2H, td), 2.8 (2H, m), 3.0 (1H, m), 3.3 (2H, m), 3.42 (2H, s), 6.9-7.5 (4H, m), 8.5 (2H, m).
MS [M+H]+ (ES+) 423
1H NMR: (CDCl3) δ 136-1.40 (2H, m), 1.87 (2H, m), 2.15 (2H m), 2.45 (2H, m), 2.76 (2H, m), 3.2 (2H, m), 3.4 (2H, s), 3.8 (1H, m), 5.4 (1H, d), 7.1-7.5 (8H m).
The title compound was prepared from 3,4-dichlorobenzyl-4-piperidone (J. Med. Chem, 1999, 42, 3629; 100 mg), 2-[4-(trifluoromethoxy)phenoxy]acetohydrazide (100 mg), sodium triacetoxyborohydride (100 mg), and 0.02 ml acetic acid, stirred together for 2 hours in dichloromethane by the method of Example 369 step ii.
MS [M+H]+ (ES+) 492
1H NMR: (CDCl3) δ 1.4-1.6 (3H, m) 1.7 (2H, m), 2.0 (2H, m) 2.7-2.9 (2H, m), 3.4 (2H, m), 4.4 (3H, m), 5.3 (1H, s) 6.9 (2H, m), 7.2-7.5 (4H, m), 7.8 (1H, d).
The title compound (29 mg) was prepared from 3,4-dichlorobenzylpiperidine-4-amine (100 mg free base), 2-[5-(3-bromopropyl)-1,2,4-oxadiazol-3-yl]pyridine (100 mg), potassium carbonate (100 mg) in dimethyl formamide (1 ml) were heated together in the microwave for 30 secs, water was added and the product extracted into dichloromethane and chromatographed on silica with ethyl acetate/methanol (9:1) as eluant.
MS [M+H]+ (ES+) 446
1H NMR: (CDCl3) δ 1.4 (2H, m) 1.7-1.9 (4H, m), 2.0-2.1 (4H, m) 2.46 (1H, m), 2.75 (2H, m), 3.1 (2H, t), 3.4 (2H, s), 7.15-7.45 (4H, m), 7.85(1H, t) 8.1 (1H, d) 8.8 (1H, d).
Prepared from N-(2-aminoethyl)-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2,2,2-trifluoroacetamide (100 mg), 3-methylsulphonylbenzoic acid (50 mg) and carbonyldiimidazole (40 mg). The product obtained was stirred together with sodium hydroxide (40 mg) in 50:50 methanol/water for 12 hrs, extracted into dichloromethane and purified by chromatography on silica with ethyl acetate/methanol (9:1) as eluant, to give the title compound (25 mg).
MS [M+H]+ (ES+) 485
1H NMR: (CDCl3) δ 1.4 (2H, m) 1.9 (2H, m), 2.0-2.1 (1H, m) 2.6 (1H, m), 2.8 (2H, m), 2.95 (2H, m) 3.1 (3H, m) 3.4 (2H, s), 3.6 (2H, m), 7.15 (2H, m), 7.4 (2H, m), 7.65(1H, t) 8.1 (2H d) 8.4 (1H, d).
MS [M+H]+ (ES+) 493
1H NMR: (CDCl3) δ 1.6 (2H, m), 1.87 (2H, m), 2.25 (2H m), 2.65 (2H, m), 2.86 (96(2H, m), 3.14 (2H, m), 3.5 (2H, s), 3.85 (1H, m), 6.0 (1H, m) 7.23 (1H, m), 7.4 (3H m), 7.45 (1H m), 8.0 (2H m).
MS [M+H]+ (ES+) 394
1H NMR: (CDCl3) δ 1.46 (2H, m), 1.8 (2H, m), 2.15 (2H m), 2.75 (4H, m), 3.3 (2H m), 3.45 (2H, s), 3.8 (1H, m), 6.05 (1H, m), 7.1 (2H, m) 7.38 (1H, m), 7.45 (1H m), 8.65 (2H m)
MS [M+H]+ (ES+) 497
1H NMR: (CDCl3) δ 1.4-1.5 (2H, m), 1.9 (2H, m), 2.15 (2H m), 2.65 (2H, m), 2.78 (2H m), 3.1 (3H s), 3.35 (2H m), 3.4 (2H, s), 3.8 (1H, m), 5.55 (1H, m), 7.16 (1H, m) 7.38 (2H, m), 8.05 (2H m), 8.2 (2H m).
MS [M+H]+ (ES+) 427
1H NMR: (CDCl3) δ 1.4 (2H, m), 1.8-1.9 (2H, m), 2.0 (2H, m), 2.5 (2H, td), 2.8 (2H, m), 3.0 (2H, s), 3.4 (2H, s), 3.94 (2H, s), 7.15 (1H, m), 7.4 (2H, m), 7.55 (2H, d) 7.9 (2H, d).
MS [M+H]+ (ES+) 435
1H NMR: (CDCl3) δ 1.6 (2H, m), 1.87 (2H, m), 2.05 (2H m), 2.65 (2H, m), 2.76 (4H m), 3.4 (2H, s), 3.8 (1H m), 5.65 (1H, m), 7.0 (1H, m), 7.1 (1H, m), 7.38 (2H, d), 7.7 (1H m), 8.2 (1H m), 8.27 (1H m), 8.65 (1H m).
MS [M+H]+ (ES+) 461
1H NMR: (CDCl3) δ 1.50 (2H, m), 1.87 (2H, m), 2.15 (2H m), 2.65 (2H, m), 3.4 (2H, s), 3.85 (1H m), 4.0 (2H, s), 7.15 (1H, d) 73-7.5 (6H, m), 7.9 (2H d).
MS [M+H]+ (ES+) 461
1H NMR: (CDCl3): δ 1.45 (2H, m), 1.90 (2H, m), 2.15 (2H m), 2.65 (2H, m), 3.25 (2H, s), 3.7 (2H, s), 3.85 (1H, m), 7.15 (2H, m) 7.4 (2H, d), 7.5 (3H m), 8.0 (2H m).
MS [M+H]+ (ES+) 428
1H NMR: (CDCl3) δ 1.36-1.45 (2H, m), 2.0 (2H, m), 2.1-2.2 (2H, t), 2.7-2.85 (4H, m), 3.34 (2H, d), 3.4(2H, d), 3.8 (1H, m), 5.6 (1H, d), 7.0-7.2 (3H m), 7.4 (1H m), 7.8 (1H, m) 8.1 (1H, d), 8.8 (1H, d)
The sub-title compound (800 mg) was prepared from 3,4-dichlorobenzyl-4-piperidone (1.3 g) tert-butyl 2-aminoethylcarbamate (0.8 g), sodium triacetoxyborohydride (10 mg), and 0.02 ml acetic acid, stirred together for 2 hrs in dichloromethane. The sub-titled compound was isolated by standard procedures.
MS [M+H]+ (ES+) 402
A mixture of the above amine (800 mg), and triethylamine (0.5 ml) in dichloromethane (50 ml), treated with trifluoroacetic anhydride (420 mg) over 30 mins, evaporated to dryness and dichloromethane (20 ml) and trifluoroacetic acid (2 ml) added, stirred for 3 hrs, then neutralised with aqueous sodium bicarbonate, the organic phase separated, dried and evaporated to give the title compound (250 mg) as a yellow oil.
MS [M+H]+ (ES+) 496/8
The title compound (30 mg) was prepared from the product above (40 mg) 3-methoxybenzoyl chloride (20 mg) and triethylamine (50 mg) using one of the methods described above.
MS [M+H]+ (ES+) 580
1H NMR: (CDCl3) δ 0.9 (6H, m) 1.2-1.4 (6H, m), 1.6-1.85 (4H, m) 2.8 (1H, m), 3.3 (4H, m), 3.6-3.8 (5H, m), 3.8 (2H, s), 7.0 (1H, m), 7.1 (1H, m), 7.35-7.45 (3H, m), 8.25(1H, t).
Further compounds of formula (I), all according to formula (Ic), are shown in the table below.
Pharmacological Analysis
Calcium Flux [Ca2+]i assay
a) Human Eosinophils
Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J. Immunol. Methods, 1991, 145, 105-110). The cells were resuspended (5×106 ml−1) and loaded with 5 μM FLUO-3/AM+Pluronic F127 2.2 μl/ml (Molecular Probes) in low potassium solution (LKS; NaCl 118 mM, MgSO4 0.8 mM, glucose 5.5 mM, Na2CO3 8.5 mM, KCl 5 mM, HEPES 20 mM, CaCl2 1.8 mM, BSA 0.1%, pH 7.4) for one hour at room temperature. After loading, cells were centrifuged at 200 g for 5 min and resuspended in LKS at 2.5×106 Ml−1. The cells were then transferred to 96 well FLIPr plates (Poly-D-Lysine plates from Becton Dickinson pre-incubated with 5 μM fibronectin for two hours) at 100 ml/well. The plate was centrifuged at 200 g for 5 min and the cells were washed twice with LKS (200 μl; room temperature).
A compound of the Examples was pre-dissolved in dimethylsulphoxide and added to a final concentration of 0.1% (v/v) dimethylsulphoxide. Assays were initiated by the addition of an A50 concentration of eotaxin and the transient increase in fluo-3 fluorescence (IEx=490 nm and IEm=520 nm) monitored using a FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, U.S.A).
b) Human Monocytes
Human monocytes were isolated from EDTA anticoagulated peripheral blood as previously described (Cunoosamy & Holbrook J. Leukocyte Biology, 1998, S2, 13). Cells were resuspended (5×106 ml−1) in LKS and loaded with 5 μM FLUO3/AM+Pluronic F127 2.2 μl/ml (Molecular Probes) for one hour at room temperature. After loading, cells were centrifuged at 200 g for 5 min and resuspended in LKS at 0.5×106 ml−1. The cells were then transferred to 96 well FLIPr plates (Costar). To each well 100 μl of cells were added at a concentration of 0.5×106 ml−1. The plates were centrifuged (200 g, 5 mins; room temperature) to allow the cells to adhere. After centrifugation the cells were washed twice with LKS (200 μl; room temperature).
A compound of the Examples was pre-dissolved in dimethylsulphoxide and added to a final concentration of 0.1% (v/v) dimethylsulphoxide. Assays were initiated by the addition of an A50 concentration of MIP-1α and the transient increase in fluo-3 fluorescence (IEx=490 nm and IEm=520 nm) monitored using a FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, U.S.A).
The compounds of the Examples were found to be antagonists of the eotaxin mediated [Ca2+]i in human eosinophils and/or antagonists of the MIP-1α mediated [Ca2+]i in human monocytes.
Human Eosinophil Chemotaxis
Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J. Immunol. Methods, 1991, 145 105-110). The cells were resuspended at 10×106 ml−1 in RPMI containing 200 IU/ml penicillin, 200 μg/ml streptomycin sulphate and supplemented with 10% HIFCS, at room temperature.
Eosinophils (700 μl) were pre-incubated for 15 mins at 37° C. with 7 μl of either vehicle or compound (100× required final concentration in 10% dimethylsulphoxide). The chemotaxis plate (ChemoTx, 3 μm pore, Neuroprobe) was loaded by adding 28 μl of a concentration of eotaxin (0.1 to 100 nM) containing a concentration of a compound according to the Examples or solvent to the lower wells of the chemotaxis plate. The filter was then placed over the wells and 25 μl of eosinophil suspension were added to the top of the filter. The plate was incubated for 1 hr at 37° C. in a humidified incubator with a 95% air/5% CO2 atmosphere to allow chemotaxis.
The medium, containing cells that had not migrated, was carefully aspirated from above the filter and discarded. The filter was washed once with phosphate buffered saline (PBS) containing 5 mM EDTA to remove any adherent cells. Cells that had migrated through the filter were pelleted by centrifugation (300×g for 5 mins at room temperature) and the filter removed and the supernatant transferred to each well of a 96-well plate (Costar). The pelleted cells were lysed by the addition of 28 μl of PBS containing 0.5% Triton×100 followed by two cycles of freeze/thawing. The cell lysate was then added to the supernatant. The number of eosinophils migrating was quantified according to the method of Strath et al., J. Immunol. Methods, 1985, 83, 209 by measuring eosinophil peroxidase activity in the supernatant.
Certain compounds of the Examples were found to be antagonists of the eotaxin mediated human eosinophil chemotaxis.
| Number | Date | Country | Kind |
|---|---|---|---|
| 9902987-8 | Aug 1999 | SE | national |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10069215 | Mar 2002 | US |
| Child | 11081201 | Mar 2005 | US |
